Hereditary haemochromatosis: Prevalence and characterization of the disease in a tertiary hospital in Aragon

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"apellidos" => "González Tarancón" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Luis" "apellidos" => "Rello Varas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "M. del Valle" "apellidos" => "Recasens Flores" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 5 => array:3 [ "nombre" => "Silvia" "apellidos" => "Izquierdo Álvarez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Clinical Biochemistry, Hospital Universitario Miguel Servet, Zaragoza, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Genetic Section, Department of Clinical Biochemistry, Hospital Universitario Miguel Servet, Zaragoza, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Hematology and Hemotherapy, Hospital Universitario Miguel Servet, Zaragoza, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Hemocromatosis hereditaria: prevalencia y caracterización de la enfermedad en un hospital terciario en Aragón" ] ] "textoCompleto" => "IntroductionHFE haemochromatosis (HC) is the cause of approximately 85–90% of HC cases. The remaining 10–15% are due to variants in other non-HFE genes.<a class="elsevierStyleCrossRef" href="#bib0140">1</a> In recent years, increasing emphasis has been placed on addressing the so-called non-classical forms of HC or HC non-HFE caused by alterations in the HJV, HAMP, TRF2, SLC40A1, and BMP6 genes.<a class="elsevierStyleCrossRefs" href="#bib0145">2–4</a>According to the current Online Mendelian Inheritance in Man (OMIM) classification,<a class="elsevierStyleCrossRef" href="#bib0160">5</a> HC type 2A (OMIM# 602390) is due to mutations in the HJV gene, located on chromosome 1q21.1 (<a href="ncbi-n:NM_213653.3">NM_213653.3</a>), while HC type 2B (OMIM# 613313) is due to mutations in the HAMP gene, located on chromosome 19q13.12 (<a href="ncbi-n:NM_021175.2">NM_021175.2</a>). Both are genetic disorders inherited in an autosomal recessive (AR) manner. Clinically, they appear as juvenile HCs with an increased transferrin saturation index (TSI) and serum ferritin. They also present iron deposits in hepatocytes. Cardiac symptoms and hypogonadism predominate over liver symptoms.<a class="elsevierStyleCrossRefs" href="#bib0160">5–7</a> HC type 3 (OMIM# 604250) is due to mutations in the TFR2 gene, located on chromosome 7q22.1 (<a href="ncbi-n:NM_003277.3">NM_003277.3</a>). It is also an AR disorder, and its clinical presentation is similar to HC HFE. However, they differ in the onset, as in this case, it is somewhat earlier and more severe, with a predominance of liver symptoms. Levels of TSI, serum ferritin, and iron are also elevated in hepatocytes.<a class="elsevierStyleCrossRefs" href="#bib0160">5–7</a> Last, HC type 4A (OMIM# 606069) is due to mutations in the SLC40A1 gene, located in chromosome 2q32.2 (<a href="ncbi-n:NM_014585.5">NM_014585.5</a>). It follows an autosomal dominant (AD) inheritance pattern, unlike the other types. Iron mainly accumulates in Kupffer cells and macrophages, affecting the reticuloendothelial system and triggering spleen and liver manifestations. Patients have elevated serum ferritin but normal or low TSI levels.<a class="elsevierStyleCrossRefs" href="#bib0160">5–7</a> In the early stages of the disease, phlebotomies are not recommended in these patients, as they often develop anaemia.<a class="elsevierStyleCrossRef" href="#bib0175">8</a> While HC type 4B, also due to mutation in SLC40A1 gene. The clinical presentation is like HH type 1 with elevate ferritin levels, elevate transferrin saturation index and liver iron accumulation, especially in the hepatocyte. It also can affect children. The disease has a good prognosis when the treatment is received before developing organic complications due to iron accumulation.<a class="elsevierStyleCrossRefs" href="#bib0150">3,6,9</a>Some articles have suggested another type of HC associated with mutations in the BMP6 gene, located on chromosome 6p24.3. Similar to HC type 4, this type is also inherited in an AD manner. A study carried out in 70 patients showed three missense mutations in the BMP6 gene (pPro95Ser, pLeu96Pro, p.Gln113Glu). Patients had moderate increases in serum ferritin levels and hepatic iron, without any other genetic variants for HC.<a class="elsevierStyleCrossRef" href="#bib0185">10</a> Other studies have found new mutations in the BMP6 gene (p. Glu112Gln, p. Arg257His, p. Q118dup),<a class="elsevierStyleCrossRefs" href="#bib0190">11,12</a> confirming their association with the development of hyperferritinemia.Due to the implementation of second-level genetic tests, such as NGS and MLPA, using targeted panels/exomes with genes involved in iron metabolism, the number of reported new mutations in non-HFE genes is increasing<a class="elsevierStyleCrossRefs" href="#bib0200">13–15</a> to such an extent that a new classification based on the genotype–phenotype correlation has been proposed. According to this new Heidelberg classification of 2019, we found four subtypes: HC related to HFE, caused by mutations in the HFE gene; HC unrelated to HFE due to mutations in non-HFE genes (HJV, HAMP, TRF2, and SLC40A); digenic HC, caused by compound heterozygosity with mutations in two different genes (HFE and/or non-HFE), and molecularly undefined HC, when the genetic origin is unknown.<a class="elsevierStyleCrossRef" href="#bib0215">16</a>The objectives of the present study are various:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1.To estimate the prevalence of HC HFE NM_000410.4: c.845G>A (p.Cys282Tyr) and NM_000410.4: c.187C>G (p.His63Asp) variants on patient with clinical manifestations of iron overload attending our hospital.</li><li class="elsevierStyleListItem" id="lsti0010">2.To estimate the prevalence of appearance of non-classical HFE gene variations and non-HFE genes (HJV, HAMP, TRF2, SLC40A1, BMP6) variations on patient with clinical manifestations of iron overload attending our hospital.</li><li class="elsevierStyleListItem" id="lsti0015">3.To predict the deleterious effect on the protein of those non-classic HFE and non-HFE variants found.</li><li class="elsevierStyleListItem" id="lsti0020">4.To established a genotype–phenotype correlation and to evaluated the findings with the clinical context of the patients.</li></ul>Therefore, the present study allows us to create a picture about the genetic heterogeneity of HC in our population.Materials and methodsSubjectsWe conducted a retrospective descriptive study between 2006 and 2020 (15 years). There were included all those patients who underwent a genetic study under suspicion of HC. The target population includes patients with a request for a genetic study of hemochromatosis who have been referred by a specialist in Digestive Medicine, Haematology, Internal Medicine or Clinical Genetic Biochemistry. The patients belonged to Health Sector Zaragoza II and attended genetic consultation at Miguel Servet University Hospital. It is a tertiary hospital, reference hospital for the approach of HC in Aragon.According to the clinical practice of the hospital, the criteria for carrying out a genetic study of genes associated to HC was:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025">-To present biochemical alteration of iron metabolism parameters: increased serum iron (>150μg/dL), increased TSI (≥45%) in at least two determinations.</li><li class="elsevierStyleListItem" id="lsti0030">-And/or increased ferritin in at least two determinations in a period of six months between both determinations.</li></ul>First, it was performed the study of classic HFE genes (C282Y/H63D). Then, if the previous result was negative and/or the clinical manifestations suggested it, the clinicians (digestive doctor, haematologist, internist, clinical geneticist) could expand the study to non-HFE genes. When studying other family members of patients with non-HFE variants, the genetic study was centred only in searching the variant found in the familiar case.There were excluded all patients with a genetic study who had been referred from primary care. And/or those patients who did not meet the requirements of the protocol for the diagnostic approach to hyperferritinemia and hereditary hemochromatosis established in the hospital.These criteria were based on the clinical practice guidelines and recommendations of the following societies: the European Association for the Study of the Liver (EASL) (2010), the American Association for the Study of Liver Diseases (AASLD) (2011), the European Molecular Genetics Quality Network (EMQN) (2016), and the American College of Gastroenterology (ACG) (2019).Genetic testingFor the classic mutation of the HFE gene (C282Y/H63D). The analysis was performed at our laboratory. DNA was obtained from the sample in an automated manner on a QIAsymphony SP using the QIAsymphony DNA Midi kit QUIAGEN®, Werfen Group. Subsequently, the quantification of the DNA obtained was performed using QUAWELL UV SPECTROPHOTOMETER Q3000. The study of C282Y/H63D mutations of the hemochromatosis (HFE) gene, LRG_748t1 (<a href="ncbi-n:NM_000410.3">NM_000410.3</a>) (NP_000401.1), was carried out by RT-PCR (Real Time PCR) using the GenVinSet HFE-C282Y/H63D kits (ref. GVS-H63D-48; ref. GVS-C282Y-48), Blackhills Diagnostic Resources S.L., in the LightCycler 96 equipment (Diagnostica Longwood) using the LightCycler® 96 v1.1 software. The detection method used is based on a PCR with specific primers for exon 2 (His63Asp) and exon 4 (Cys282Tyr) of the HFE gene and two Taqman® probes specific for the normal gene and the mutated gene, respectively.For those patients who underwent additional genetic studies, non-HFE genes causing disease development (HFE2, HAMP, TFR2, SLC40A1, BMP6) were analysed in LABGENETICS, Madrid-Spain. DNA was obtained from the sample in an automated manner on a Maxwell® 16 System using the Maxwell® RSC Blood DNA kit (Promega). Subsequently, the quantification of the DNA obtained by fluorimetry was performed using Qubit Fluorimetric Quantitation with the Qubit dsDNA BR Assay Kit. For spot detection, a haemochromatosis panel (IAD188248) was used for the preparation of libraries designed using Ion AmpliSeq™ technology (Thermo Fisher Scientific), with a horizontal coverage of 100.00% of the coding region and 25bp of the adjacent intronic regions of the 8 genes included in this panel, with a size of 17.74 Kb and comprising 66 amplicons. For the preparation of libraries, the Ion AmpliSeq™ Library Kit 2.0 was used. Library quantification was performed in a 7500 Fast Real-Time PCR System from Applied Biosystems®. An emulsion and enrichment PCR was performed using the “Ion PGM™ Hi-Q™ View OT2 Kit” and “Ion PGM™ Enrichment Beads” kits in an automated manner on an Ion OneTouch 2.0 System. Sequencing was performed on the Ion PGM System platform using the Ion PGM Hi-Q View Sequencing Kit on an Ion 316 Chip v2. All potentially pathogenic SNVs and indels were validated by Sanger sequencing.For the analysis of large deletions/duplications, PCR amplification of different coding regions of the HFE, HFE2, SLC40A1, HAMP, and TFR2 genes was performed using the MLPA technique with P347-A3 kits from the MRC-Netherlands. The detection of the amplified products was performed by capillary electrophoresis under denaturing conditions in an Applied Biosystems® 3500 DX Genetic Analyser.Variants were named according to the Human Genome Variation Society (HGVS) recommendations (<a href="http://varnomen.hgvs.org/">http://varnomen.hgvs.org/</a>).Prevalence studyPrevalence was calculated using the statistics software Microsoft® Excel® for Microsoft 365 MSO (version 2306 build 16.0.16529.20100).For prevalence calculation of HFE HC, it was calculated the number of C282Y homozygous patients respect the total number of patients with suspected hemochromatosis who underwent genetic studies. It was also calculated the number of C282Y homozygous patients respect the total population in Health Sector Zaragoza II.For prevalence calculation of non-HFE HC, it was calculated the number of patients with non-HFE variants respect the total number of patients with suspected hemochromatosis who underwent genetic studies. It was also calculated the number of patients with non-HFE variants respect the total population in Health Sector Zaragoza II.Bioinformatic analysisThe classification of the non-HFE variants was performed using the analysis software Alamut® Visual 2.15, HGMD® Professional 2017.2, gnomAD browser, Varsome, and ClinVar. The reference sequences used to analyse the results were BMP6 (<a href="ncbi-n:NM_001718.5">NM_001718.5</a>), FTH1 (<a href="ncbi-n:NM_002032.2">NM_002032.2</a>), FTL (<a href="ncbi-n:NM_000146.3">NM_000146.3</a>), HAMP (<a href="ncbi-n:NM_021175.2">NM_021175.2</a>), HFE (<a href="ncbi-n:NM_000410.3">NM_000410.3</a>), HFE2/HJV (<a href="ncbi-n:NM_213653.3">NM_213653.3</a>), SLC40A1 (<a href="ncbi-n:NM_014585.5">NM_014585.5</a>), and TFR2 (<a href="ncbi-n:NM_003227.3">NM_003227.3</a>).All the variants found were classified according to the ACMG criteria.<a class="elsevierStyleCrossRef" href="#bib0220">17</a>Clinical variablesIt was measured clinical events by using laboratory parameters of iron metabolism, imaging test, and treatment used (phlebotomy and/or electrophoresis). Biochemical parameters: ferritin, TSI, serum iron, transferrin and C-reactive protein (CRP) were measured on an AU5800® Chemistry System (Beckman Coulter). TSI was calculated as follows: Ferritin*100/(Transferrin*1.41). Haematological parameters: haemoglobin (hb), haematocrit (ht), and mean corpuscular volume (MCV) were measured on a DxH 900® Haematology Analyser (Beckman Coulter). We took into account both magnetic resonance imaging (MRI) and laboratory results obtained just before genetic testing.It was registered the number of phlebotomies/electrophoresis needed by each patient to normalized iron metabolism parameters and the total number of phlebotomies/electrophoresis performed.ResultsHealth Sector of Zaragoza II corresponds to 377,967 population. One thousand five hundred forty-seven patients met the inclusion criteria proposed for the study. Forty-seven patients underwent further studies on non-HFE genes.Prevalence of HCThe prevalence of HFE HC genetic confirmation (C282Y homozygous) respect the total of cases was 5.95% (95 cases). The prevalence of HFE HC genetic confirmation (C282Y homozygous) respect our population was 0.025%.The prevalence of appearance of non-HFE HC variants respect the total of cases was 1.94% (30 cases). The prevalence of appearance of non-HFE HC variants respect our population was 0.008%.Prediction software resultsThere were detected 27 non-classic HC variants. Four variants in the HFE gene different from C282Y/H63D classical mutation (NM_000410.4 c.1007-47G>A, NM_000410.4 c.340+4T>C, NM_000410.4 c.82C>T, NM_000410.4 c.892+48G>A). And 23 variants in non-HFE genes (HJV, HAMP, TRF2, SLC40A1, BMP6) related to HC (NM_001718.6 c.1104G>A, NM_001718.6 c.1281+24T>C, NM_001718.6 c.337C>G, NM_001718.6 c.83G>A, NM_001718.6 c.857+12C>T, NM_000146.4 c.163T>C, NM_145277.5 c.335A>T, NM_014585.6 c.*1114T>A, NM_014585.6 c.43+68A>C, NM_014585.6 c.44-24G>C, NM_014585.6 c.533G>A, NM_014585.6 c.663T>C, NM_014585.6 c.-8C>G, NM_014585.6 c.-98G>C, NM_003227.4 c.1270+16A>G, NM_003227.4 c.1364G>A, NM_003227.4 c.1851C>T, NM_003227.4 c.1995+9G>C, NM_003227.4 c.2101C>T, NM_003227.4 c.2255G>A, NM_003227.4 c.2278G>A, NM_003227.4 c.2343G>A, NM_003227.4 c.64G>A).According to the ACMG criteria, the variants NM_000410.4 c.82C>T, NM_145277.5 c.335A>T, and NM_014585.6 c.*1114T>A were characterised as uncertain significance. In addition, the variants NM_014585.6 c.533G>A, NM_003227.4 c.2101C>T and NM_003227.4 c.2343G>A were characterised as pathogenic/likely pathogenic (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Deletereus effect on the protein of the pathogenic/likely pathogenic and uncertain significant variantsThe NM_000410.4 c.82C>T variant is a missense variant (CADD score 24.6), which generated an abnormal HFE protein in which amino acid 28 histidine has been replaced by tyrosine. This change affects a highly conserved region of the HFE protein.The NM_145277.5 c.335A>T variant is a missense variant (CADD score 28.3), which causes an abnormal HJV protein in which amino acid 112 lysine has been replaced by methionine. This change affects a highly conserved region of the HJV protein.The NM_014585.6 c.*1114T>A variant is located at the 3′UTR region in the 8 exon, position 1428 of 1602, is located in the exon 8 of the gene, it affect a non-coding region but the effect on the SLC40A1 protein generated is yet unknown, as it can possibly affect a highly conserved region of the SLC40A1 protein.The NM_014585.6 c.533G>A variant is a missense variant (CADD score 30), which causes an abnormal SLC40A1 protein in which amino acid 178 arginine has been replaced by glycine. This change affects a highly conserved region of the SLC40A1 protein.The NM_003227.4 c.2101C>T variant is a nonsense variant, in which codon 701 that codified for amino acid arginine is substituted by a termination codon. This originates a truncated protein of 700 amino acid compared to 801 of the normal one.The NM_003227.4 c.2343G>A variant is a nonsense variant, in which codon 781 that codified for amino acid tryptophan is substituted by a termination codon. This originates a truncated protein of 700 amino acid compared to 801 of the normal one.Genotype and clinical characteristics of patients with pathogenic/likely pathogenic and uncertain significant variantsThe NM_000410.4 c.82C>T variant was detected in a patient (HC21) with high serum ferritin levels (523.50ng/mL, normal range: 15–200ng/mL), but TSI and serum iron were within the normal range. She did not present any other clinical signs of iron overload, and did not need to be treated with phlebotomies.The NM_145277.5 c.335A>T variant was detected in heterozygosity in a patient (HC10) in which the MRI revealed a moderate hepatic iron overload of 25.60μFe/G. Currently, she is in treatment with phlebotomies.The NM_014585.6 c.*1114T>A variant was detected in heterozygosity in a patient (HC1) who presented altered iron metabolism parameters: ferritin 2426 ng/mL and TSI 54.72% (20–40%), in addition to a moderate hepatic iron overload seen on MRI. He needed 43 phlebotomies to normalize iron metabolism parameters.The NM_014585.6 c.533G>A variant was detected in heterozygosity in a patient (HC4) with altered ferritin levels (1098ng/mL) but normal TSI and serum iron levels. MRI also showed no iron hepatic overload. Even after treatment with phlebotomies, he received 13 in total, iron metabolism parameters did not normalize.The NM_003227.4 c.2101C>T and the NM_003227.4 c.2343G>A variants were detected in heterozygosity in a patient (HC24) who presented altered levels of ferritin (2109.10ng/mL), TSI (86.59%) and serum iron (203.00μg/dL, normal range: 60–180μg/dL). MRI also showed hepatic iron overload. He is in treatment with phlebotomies, but after receiving 13, iron metabolism parameters still have not normalized.The NM_003227.4 c.2343G>A variant was also detected in homozygosity in a patient (HC15) with long-standing hypersideremia who was diagnosed at the age of 29 with HC. She has been in treatment with phlebotomies since 1999.Genotype characterization and clinical featured of all patient mentioned above are summarised at the following tables (<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>DiscussionAs other studies before,<a class="elsevierStyleCrossRefs" href="#bib0225">18–20</a> the present study shows that the prevalence of HFE HC is lower in our population than in the North European population. Seventy-six percent of cases diagnosed with HC correspond to HFE haemochromatosis and the remaining 24% are due to variants in other non-HFE genes.Specifically, the prevalence of C282Y homozygotes in patients with symptoms of iron overload was 5.95%, a result slightly lower to that obtained by Gomez-Llorente et al. in their study in which 6.13% of subjects with abnormal iron metabolism were homozygous for the HFE C282Y variant,<a class="elsevierStyleCrossRef" href="#bib0235">20</a> probably explained by our larger sample size (1547 patients compared to 359).On the other hand, Wallace et al. provide a global prevalence of HFE and specially non-HFE hemochromatosis through pathogenic allele frequencies data.<a class="elsevierStyleCrossRef" href="#bib0140">1</a> In our case, we estimated the prevalence of the appearance of non-HFE variants in both the general population, 0.008%, and patients with symptoms of iron overload, 1.94%.It should be taken into account that only 3.17% of the patients initially studied for the C282Y/H63D mutations underwent further non-HFE studies. Due to clinical practice, not all patient with a negative result on C282Y/H63D mutations underwent further non-HFE studies. The study period is too long, and the genetic diagnosis of HC has been changing as there were found new genes causing the disease. This has led to the progressive reevaluation of some patients and the adaptation of hospital protocols to the latest clinical practice guidelines. This contributes to a heterogeneity of the genetic results obtained over the years and constitutes the main limitation of our work since the real prevalence of non-HFE variants could be misestimate.When analysing patients with a non-HFE variants and clinical manifestations of iron overload, it is surprising that only six patients (20% of the cases) presented any pathogenic/probably pathogenic or uncertain significance variant. Besides, only in three of them (10% of the cases) these variants found could explain the symptoms. The rest (27 cases) remain without genetic justification for their hyperferritinemia.In one hand we have, patient HC4 that presents the variant NM_014585.6 c.533G>A classified as pathogenic. Chandran et al. have previously described this variant in several patients who, like ours, present elevated ferritin levels but normal TSI levels. In their study, a new pathogenic mechanism was proposed. The presence of the NP_055400.1 p.Arg178Gln mutated protein reduces the ability of FPN1 to export iron without causing protein mislocalization. The amino acid p.Arg178 would be part of an interaction network modulating the conformational changes required for iron transport.<a class="elsevierStyleCrossRef" href="#bib0175">8</a> The presence of this mutation in heterozygosis is compatible with ferroportin diseases or HC type 4A and justified the clinical manifestation of our patient.Patient HC15 which presented in homozygosis the previously reported NM_003227.4 c.2343G>A variant.<a class="elsevierStyleCrossRef" href="#bib0240">21</a> In Bardou-Jaquet et al. case the NM_003227.4 c.2343G>A was presented in compound heterozygosis with another TFR2 variant (p.Arg730Cys) in a patient with early onset HC type 3, as in our case before the age of 30. In a subsequent genetic study carried out on both parents, it was found that they present the same variant in heterozygosis.In addition, patient HC 24 also presented the NM_003227.4 c.2343G>A variant in compound heterozygosis with the pathogenic variant NM_003227.4 c.2101C>T. The NM_003227.4 c.2101C>T variant has been previously describe<a class="elsevierStyleCrossRef" href="#bib0245">22</a> in a patient with similar characteristics and the presence of the mutation in homozygosis.Both variant NM_003227.4 c.2343G>A. and NM_003227.4 c.2101C>T originated respectively the truncated proteins NP_003218.2 p.Trp781Ter and NP_003218.2 p.Arg701Ter. located at the TFR dimeric domain.<a class="elsevierStyleCrossRefs" href="#bib0245">22,23</a> TFR 2 dimerization is an essential step for its normal activity, the presence of a truncated protein at this level would affect the interaction TFR2/Tf, reducing the signalling cascade for hepcidine production, and, at the end, iron accumulation. Our cases confirm HC type 3 presents with more severe and earlier iron overload complications compared with type 1 and 4b, as it was already reported.<a class="elsevierStyleCrossRefs" href="#bib0240">21,24,25</a>On the other hand, we have the case of patient HC1 who presented the uncertain significance variant (VUS) NM_014585.6 c.*1114T>A. This variant has a low allele frequency (0.001971%), and the results of various prediction algorithms suggest that the protein generated may cause disease. However, in the predictive study of relatives, it was found that a brother and both children of the proband had the same mutation. The all three were asymptomatic. If they develop symptoms of the disease, it would support the diagnosis of HC type 4, and the reclassification of the variant from VUS to possibly pathogenic. Nevertheless, for the moment until more evidence remains without a clear genetic diagnosis.Moreover, both patient HC10 and HC21 presented a VUS (NM_145277.5 c.335A>T in the case of patient HC10, and NM_000410.4 c.82C>T in the case of patient HC21). In both cases, even in the event that those variants were a pathogenic mutation, since the mode of inheritance of type 1 and type 2 Hemochromatosis is autosomal recessive, the presence of a single mutation would not be diagnostic for the development of the disease. However, as the patients presented symptoms associated with haemochromatosis, it is possible that they present another variants not yet identify.A new type of hemochromatosis has recently been included in OMIM. Hemochromatosis type 5 (OMIM# 615517) is caused by heterozygous mutation in the FTH1 gene (134770) on chromosome 11q12. The FTH1 gene codifies the synthesis of the heavy chain subunit (FTH) of the ferritin. The FTH has the ferroxidase activity centre while the light chain subunit (FTL) is responsible of the iron-storage function of the ferritin.<a class="elsevierStyleCrossRef" href="#bib0265">26</a> A mutation in the FTH1 gene was studied in a Japanese family in which the proband presented high serum ferritin level, as well as an increase in both serum iron and transferrin saturation. Iron deposition in liver, heart, and bone marrow shown on MRI and on liver.<a class="elsevierStyleCrossRef" href="#bib0270">27</a> This opens the door to the reassessment of those patients still without a clear molecular diagnosis.ConclusionWe can affirm that the prevalence of CH in our population is similar to that found in geographically close areas.Second-level genetic tests (NGS and MLPA) help in clinical practice the study of non-HFE HC cases, allowing us to find a molecular cause of iron overload.However, we count with large number of patients who present some polymorphism in genes associated to hepcidin synthesis pathway/iron metabolism routes, which even today remain without finding a molecular cause to their iron overload symptoms. For this reason, it is important to perform periodic reassessments of these patients in our clinical practice. Just as important as to review what new genes could be involved in the pathogenesis of the disease. As clinicians, we cannot forget that the final objective is not only to provide a molecular/metabolic justification to our patient but also to provide them with a clinical diagnosis of their disease.Ethical considerationsThis study was performed in accordance with the Declaration of Helsinki and it was approved by the committee of health care ethics in Aragon (CEICA) with number PI20/397. Informed consent was obtained from participants before performing the genetic study.FundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Authors’ contributionsCAM: conception and design of the study, acquisition of data, analysis and/or interpretation of data and drafting the manuscript and revising the manuscript for important intellectual content. NGR: analysis and/or interpretation of data and drafting the manuscript. RGT: analysis and/or interpretation of data and revising the manuscript for important intellectual content. LRV: analysis and/or interpretation of data and revising the manuscript for important intellectual content. VRF: conception and design of the study, acquisition of data, and revising the manuscript for important intellectual content. SIA: conception and design of the study, analysis and/or interpretation of data and revising the manuscript for important intellectual content.All authors revised and approved the manuscript final version.Conflict of interestThe authors declare that they have not conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres2202212" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1848105" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2202211" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Metodología" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1848104" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Subjects" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Genetic testing" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Prevalence study" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Bioinformatic analysis" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Clinical variables" ] ] ] 6 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Prevalence of HC" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Prediction software results" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Deletereus effect on the protein of the pathogenic/likely pathogenic and uncertain significant variants" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Genotype and clinical characteristics of patients with pathogenic/likely pathogenic and uncertain significant variants" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0075" "titulo" => "Ethical considerations" ] 10 => array:2 [ "identificador" => "sec0080" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0085" "titulo" => "Authors’ contributions" ] 12 => array:2 [ "identificador" => "sec0090" "titulo" => "Conflict of interest" ] 13 => array:2 [ "identificador" => "xack759033" "titulo" => "Acknowledgements" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2024-02-01" "fechaAceptado" => "2024-05-13" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1848105" "palabras" => array:5 [ 0 => "Haemochromatosis" 1 => "Iron overload" 2 => "Hyperferritinemia" 3 => "Next-generation sequencing" 4 => "Multiplex ligation-dependent probe amplification" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1848104" "palabras" => array:5 [ 0 => "Hemocromatosis" 1 => "Sobrecarga de hierro" 2 => "Hiperferritinemia" 3 => "Next-generation sequencing" 4 => "Multiplex ligation-dependent probe amplification" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundThe main genetic cause of iron overload is haemochromatosis (HC). In recent years, the study of non-HFE genes (HFE2, HJV, HAMP, TRF2, SLC40A1, and BMP6) has become relevant thanks to next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) techniques. Our objectives were to estimate the prevalence of both HFE (C282Y/HY63D variants) and non-HFE variants attending a tertiary hospital in Aragón, to predict the effect of the variants on the protein, and to establish a genotype–phenotype correlation evaluating with the clinical context. MethodsRetrospective descriptive study from 2006 to 2020 of patients attended at genetic consultation in a reference hospital for HC in Aragon. We calculated prevalence of HFE and non-HFE variants. We analysed non-HFE genes (HFE2, HJV, HAMP, TRF2, SLC40A1, and BMP6), used bioinformatics tools, consulted different databases and measured clinical parameters (laboratory and imaging). ResultsThe prevalence of C282Y homozygous was 5.95% respect the total of cases and 0.025% respect our population. The prevalence of non-HFE HC variants was 1.94% respect the total of cases and 0.008% respect our population. We found 27 variants in non-HFE genes and 4 in HFE gene, of which 6 were classified as variant of uncertain clinical significance (VUS), or likely pathogenic or pathogenic according to the ACMG classification criteria. ConclusionOur prevalence results are as expected, and similar to those obtained by other studies. Although some of the genetic findings explain the clinical symptoms of some of our patients, we remain have a high number of patients without a clear molecular diagnosis." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "AntecedentesLa principal causa genética de sobrecarga de hierro es la hemocromatosis. En los últimos años ha ganado importancia el estudio de los genes no-HFE (HFE2, HJV, HAMP, TRF2, SLC40A1 y BMP6) gracias a las técnicas next-generation sequencing (NGS) y multiplex ligation-dependent probe amplification (MLPA). Nuestros objetivos son estimar la prevalencia de las variantes HFE (C282Y/HY63D) y no-HFE en nuestro hospital, predecir el efecto de las variantes en la proteína y establecer una correlación genotipo-fenotipo evaluando con el contesto clínico. MetodologíaEstudio descriptivo retrospectivo desde 2006 a 2020 de pacientes que asistieron a consulta de genética en un hospital terciario en Aragón. Calculamos la prevalencia de las variantes HFE y no-HFE. Analizamos los genes no-HFE (HFE2, HJV, HAMP, TRF2, SLC40A1 y BMP6) usando herramientas bioinformáticas, consultando diferentes bases de datos y midiendo parámetros clínicos (laboratorio e imagen). ResultadosLa prevalencia de homocigotos C282Y fue del 5,95% respecto del total de casos y del 0,025% respecto de la población en Aragón. La prevalencia de variantes no-HFE fue del 1,94% respecto al total de casos y del 0,008% respecto de la población en Aragón. Encontramos 27 variantes en genes no-HFE y 4 en genes HFE, de las cuales 6 fueron clasificadas como de significado incierto, como probablemente patogénicas o como patogénicas según los criterios de clasificación de la ACMG. ConclusiónNuestros resultados de prevalencia fueron los esperados y similares a aquellos obtenidos en otros estudios. Aunque algunos de los hallazgos genéticos explican los síntomas clínicos de algunos de nuestros pacientes, seguimos teniendo un elevado número de pacientes sin un diagnóstico molecular claro." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Metodología" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Transcript \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HGVS coding \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SNP ID \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Coding impact \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Allele frequency \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ACMG classification \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Classifying criteria \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HFE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_000410.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.82C>T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Missense (CADD score 24.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.000657 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uncertain significance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PP3/PM1/PM2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HJV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_145277.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.335A>T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Missense (CADD score 28.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not found \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uncertain significance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PM2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SLC40A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_014585.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.*1114T>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs1255810280 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Unknown \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.001971 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uncertain significance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PM2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SLC40A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_014585.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.533G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs1449300685 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Missense (CADD score 30) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not found \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathogenic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PS3/PP3/PP5/PM1/PM2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TFR2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_003227.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.2101C>T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs946552921 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nonsense \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.003942 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathogenic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PVS1/PP5/PM2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TFR2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_003227.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.2343G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs768907730 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nonsense \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.003284 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Likely pathogenic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PVS1/PP5/PM2 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3593868.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Non-HFE and non-classic HFE variants description." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case number \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variant \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Genotype \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ACMG classification \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HH1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SLC40A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_014585.6 c.*1114T>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uncertain significance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HH4<a class="elsevierStyleCrossRef" href="#tblfn0005">†</a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SLC40A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_014585.6 c.533G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathogenic \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TFR2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_003227.4 c.1364G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Likely benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TFR2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_003227.4 c.1995+9G>C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Likely benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HH10</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SLC40A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_014585.6 c.44-24G>C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HJV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_145277.5 c.335A>T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uncertain significance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HH15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TFR2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_003227.4 c.2343G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Homozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Likely pathogenic \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HH21</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SLC40A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_014585.6 c.44-24G>C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SLC40A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_014585.6 c.-8C>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SLC40A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_014585.6 c.-98G>C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HFE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_000410.4 c.82C>T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uncertain significance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">FTL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_000146.4 c.163T>C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Homozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HH24</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SLC40A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_014585.6 c.44-24G>C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Homozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SLC40A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_014585.6 c.43+68A>C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SLC40A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_014585.6 c.-8C>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SLC40A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_014585.6 c.-98G>C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BMP6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_001718.6 c.337C>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BMP6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_001718.6 c.1104G>C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Likely benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BMP6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_001718.6 c.1281+24T>C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Homozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HFE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_000410.4 c.340+4T>C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HFE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_000410.4 c.1007-47G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TFR2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_003227.4 c.2343G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Likely pathogenic \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TFR2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_003227.4 c.2101C>T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathogenic \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TFR2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_003227.4 c.1851C>T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">FTL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NM_000146.4 c.163T>C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3593866.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "†" "nota" => "Deceased." ] ] ] "descripcion" => array:1 [ "en" => "Genotype characterization of patient with pathogenic/likely pathogenic and uncertain significant variants." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Case number \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Age at 1st visit \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="8" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Iron metabolism</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Magnetic resonance imaging</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Ferritin15–200ng/mL \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TSI20–40% \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Serum iron60–180μg/dL \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Transferrin20–360mg/dL \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PCR≤0.50mg/dL \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HB12–16.5g/dL \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HTO36–46% \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MCV80100fL \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MRI<a class="elsevierStyleCrossRef" href="#tblfn0015">*</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MRI μFe/G \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HH1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2426.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">54.72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">150.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">191.90 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17.40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51.20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">93.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60+/−30 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HH4<a class="elsevierStyleCrossRef" href="#tblfn0010">†</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">69 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1098.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28.03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">85.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">212.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15.50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">47.60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">87.90 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HH10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">440.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">95.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">240.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">166.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND<a class="elsevierStyleCrossRef" href="#tblfn0020">**</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND<a class="elsevierStyleCrossRef" href="#tblfn0020">**</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">101.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HH11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">53 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">766.40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30.68 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">99.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">225.90 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15.80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">47.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">89.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HH15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">312.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">83.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">240.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">194.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND<a class="elsevierStyleCrossRef" href="#tblfn0020">**</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND<a class="elsevierStyleCrossRef" href="#tblfn0020">**</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">97.80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; 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Original article

Hereditary haemochromatosis: Prevalence and characterization of the disease in a tertiary hospital in Aragon

Hemocromatosis hereditaria: prevalencia y caracterización de la enfermedad en un hospital terciario en Aragón

Claudia Abadía Molinaa,

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cabadiamo@salud.aragon.es

Corresponding author.

, Nuria Goñi Rosa, Ricardo González Tarancónb, Luis Rello Varasa, M. del Valle Recasens Floresc, Silvia Izquierdo Álvarezb

a Department of Clinical Biochemistry, Hospital Universitario Miguel Servet, Zaragoza, Spain

b Genetic Section, Department of Clinical Biochemistry, Hospital Universitario Miguel Servet, Zaragoza, Spain

c Department of Hematology and Hemotherapy, Hospital Universitario Miguel Servet, Zaragoza, Spain

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    "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
    "titulo" => "Hereditary haemochromatosis&#58; Prevalence and characterization of the disease in a tertiary hospital in Aragon"
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        "autoresLista" => "Claudia Abad&#237;a Molina, Nuria Go&#241;i Ros, Ricardo Gonz&#225;lez Taranc&#243;n, Luis Rello Varas, M&#46; del Valle Recasens Flores, Silvia Izquierdo &#193;lvarez"
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            "nombre" => "Claudia"
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            "entidad" => "Department of Clinical Biochemistry&#44; Hospital Universitario Miguel Servet&#44; Zaragoza&#44; Spain"
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            "entidad" => "Genetic Section&#44; Department of Clinical Biochemistry&#44; Hospital Universitario Miguel Servet&#44; Zaragoza&#44; Spain"
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            "entidad" => "Department of Hematology and Hemotherapy&#44; Hospital Universitario Miguel Servet&#44; Zaragoza&#44; Spain"
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    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Hemocromatosis hereditaria&#58; prevalencia y caracterizaci&#243;n de la enfermedad en un hospital terciario en Arag&#243;n"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">HFE haemochromatosis &#40;HC&#41; is the cause of approximately 85&#8211;90&#37; of HC cases&#46; The remaining 10&#8211;15&#37; are due to variants in other non-HFE genes&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">1</span></a> In recent years&#44; increasing emphasis has been placed on addressing the so-called non-classical forms of HC or HC non-HFE caused by alterations in the <span class="elsevierStyleItalic">HJV</span>&#44; <span class="elsevierStyleItalic">HAMP</span>&#44; <span class="elsevierStyleItalic">TRF2</span>&#44; <span class="elsevierStyleItalic">SLC40A1</span>&#44; and <span class="elsevierStyleItalic">BMP6</span> genes&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2&#8211;4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">According to the current Online Mendelian Inheritance in Man &#40;OMIM&#41; classification&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">5</span></a> HC type 2A &#40;OMIM&#35; 602390&#41; is due to mutations in the <span class="elsevierStyleItalic">HJV</span> gene&#44; located on chromosome 1q21&#46;1 &#40;<a href="ncbi-n:NM_213653.3">NM&#95;213653&#46;3</a>&#41;&#44; while HC type 2B &#40;OMIM&#35; 613313&#41; is due to mutations in the <span class="elsevierStyleItalic">HAMP</span> gene&#44; located on chromosome 19q13&#46;12 &#40;<a href="ncbi-n:NM_021175.2">NM&#95;021175&#46;2</a>&#41;&#46; Both are genetic disorders inherited in an autosomal recessive &#40;AR&#41; manner&#46; Clinically&#44; they appear as juvenile HCs with an increased transferrin saturation index &#40;TSI&#41; and serum ferritin&#46; They also present iron deposits in hepatocytes&#46; Cardiac symptoms and hypogonadism predominate over liver symptoms&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">5&#8211;7</span></a> HC type 3 &#40;OMIM&#35; 604250&#41; is due to mutations in the <span class="elsevierStyleItalic">TFR2</span> gene&#44; located on chromosome 7q22&#46;1 &#40;<a href="ncbi-n:NM_003277.3">NM&#95;003277&#46;3</a>&#41;&#46; It is also an AR disorder&#44; and its clinical presentation is similar to HC HFE&#46; However&#44; they differ in the onset&#44; as in this case&#44; it is somewhat earlier and more severe&#44; with a predominance of liver symptoms&#46; Levels of TSI&#44; serum ferritin&#44; and iron are also elevated in hepatocytes&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">5&#8211;7</span></a> Last&#44; HC type 4A &#40;OMIM&#35; 606069&#41; is due to mutations in the <span class="elsevierStyleItalic">SLC40A1</span> gene&#44; located in chromosome 2q32&#46;2 &#40;<a href="ncbi-n:NM_014585.5">NM&#95;014585&#46;5</a>&#41;&#46; It follows an autosomal dominant &#40;AD&#41; inheritance pattern&#44; unlike the other types&#46; Iron mainly accumulates in Kupffer cells and macrophages&#44; affecting the reticuloendothelial system and triggering spleen and liver manifestations&#46; Patients have elevated serum ferritin but normal or low TSI levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">5&#8211;7</span></a> In the early stages of the disease&#44; phlebotomies are not recommended in these patients&#44; as they often develop anaemia&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">8</span></a> While HC type 4B&#44; also due to mutation in SLC40A1 gene&#46; The clinical presentation is like HH type 1 with elevate ferritin levels&#44; elevate transferrin saturation index and liver iron accumulation&#44; especially in the hepatocyte&#46; It also can affect children&#46; The disease has a good prognosis when the treatment is received before developing organic complications due to iron accumulation&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">3&#44;6&#44;9</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Some articles have suggested another type of HC associated with mutations in the <span class="elsevierStyleItalic">BMP6</span> gene&#44; located on chromosome 6p24&#46;3&#46; Similar to HC type 4&#44; this type is also inherited in an AD manner&#46; A study carried out in 70 patients showed three <span class="elsevierStyleItalic">missense</span> mutations in the <span class="elsevierStyleItalic">BMP6</span> gene &#40;pPro95Ser&#44; pLeu96Pro&#44; p&#46;Gln113Glu&#41;&#46; Patients had moderate increases in serum ferritin levels and hepatic iron&#44; without any other genetic variants for HC&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">10</span></a> Other studies have found new mutations in the <span class="elsevierStyleItalic">BMP6</span> gene &#40;p&#46; Glu112Gln&#44; p&#46; Arg257His&#44; p&#46; Q118dup&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">11&#44;12</span></a> confirming their association with the development of hyperferritinemia&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Due to the implementation of second-level genetic tests&#44; such as NGS and MLPA&#44; using targeted panels&#47;exomes with genes involved in iron metabolism&#44; the number of reported new mutations in non-HFE genes is increasing<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">13&#8211;15</span></a> to such an extent that a new classification based on the genotype&#8211;phenotype correlation has been proposed&#46; According to this new Heidelberg classification of 2019&#44; we found four subtypes&#58; HC related to HFE&#44; caused by mutations in the <span class="elsevierStyleItalic">HFE</span> gene&#59; HC unrelated to HFE due to mutations in <span class="elsevierStyleItalic">non-HFE</span> genes &#40;<span class="elsevierStyleItalic">HJV</span>&#44; <span class="elsevierStyleItalic">HAMP</span>&#44; <span class="elsevierStyleItalic">TRF2</span>&#44; and <span class="elsevierStyleItalic">SLC40A</span>&#41;&#59; digenic HC&#44; caused by compound heterozygosity with mutations in two different genes &#40;HFE and&#47;or non-HFE&#41;&#44; and molecularly undefined HC&#44; when the genetic origin is unknown&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">16</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The objectives of the present study are various&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0030" class="elsevierStylePara elsevierViewall">To estimate the prevalence of HC <span class="elsevierStyleItalic">HFE</span> NM&#95;000410&#46;4&#58; c&#46;845G&#62;A &#40;p&#46;Cys282Tyr&#41; and NM&#95;000410&#46;4&#58; c&#46;187C&#62;G &#40;p&#46;His63Asp&#41; variants on patient with clinical manifestations of iron overload attending our hospital&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0035" class="elsevierStylePara elsevierViewall">To estimate the prevalence of appearance of non-classical HFE gene variations and non-HFE genes &#40;<span class="elsevierStyleItalic">HJV</span>&#44; <span class="elsevierStyleItalic">HAMP</span>&#44; <span class="elsevierStyleItalic">TRF2</span>&#44; <span class="elsevierStyleItalic">SLC40A1</span>&#44; <span class="elsevierStyleItalic">BMP6</span>&#41; variations on patient with clinical manifestations of iron overload attending our hospital&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#46;</span><p id="par0040" class="elsevierStylePara elsevierViewall">To predict the deleterious effect on the protein of those non-classic HFE and non-HFE variants found&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4&#46;</span><p id="par0045" class="elsevierStylePara elsevierViewall">To established a genotype&#8211;phenotype correlation and to evaluated the findings with the clinical context of the patients&#46;</p></li></ul></p><p id="par0050" class="elsevierStylePara elsevierViewall">Therefore&#44; the present study allows us to create a picture about the genetic heterogeneity of HC in our population&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Subjects</span><p id="par0055" class="elsevierStylePara elsevierViewall">We conducted a retrospective descriptive study between 2006 and 2020 &#40;15 years&#41;&#46; There were included all those patients who underwent a genetic study under suspicion of HC&#46; The target population includes patients with a request for a genetic study of hemochromatosis who have been referred by a specialist in Digestive Medicine&#44; Haematology&#44; Internal Medicine or Clinical Genetic Biochemistry&#46; The patients belonged to Health Sector Zaragoza II and attended genetic consultation at Miguel Servet University Hospital&#46; It is a tertiary hospital&#44; reference hospital for the approach of HC in Aragon&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">According to the clinical practice of the hospital&#44; the criteria for carrying out a genetic study of genes associated to HC was&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0065" class="elsevierStylePara elsevierViewall">To present biochemical alteration of iron metabolism parameters&#58; increased serum iron &#40;&#62;150<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;dL&#41;&#44; increased TSI &#40;&#8805;45&#37;&#41; in at least two determinations&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0070" class="elsevierStylePara elsevierViewall">And&#47;or increased ferritin in at least two determinations in a period of six months between both determinations&#46;</p></li></ul></p><p id="par0075" class="elsevierStylePara elsevierViewall">First&#44; it was performed the study of classic HFE genes &#40;C282Y&#47;H63D&#41;&#46; Then&#44; if the previous result was negative and&#47;or the clinical manifestations suggested it&#44; the clinicians &#40;digestive doctor&#44; haematologist&#44; internist&#44; clinical geneticist&#41; could expand the study to non-HFE genes&#46; When studying other family members of patients with non-HFE variants&#44; the genetic study was centred only in searching the variant found in the familiar case&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">There were excluded all patients with a genetic study who had been referred from primary care&#46; And&#47;or those patients who did not meet the requirements of the <span class="elsevierStyleItalic">protocol for the diagnostic approach to hyperferritinemia and hereditary hemochromatosis</span> established in the hospital&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">These criteria were based on the clinical practice guidelines and recommendations of the following societies&#58; the European Association for the Study of the Liver &#40;EASL&#41; &#40;2010&#41;&#44; the American Association for the Study of Liver Diseases &#40;AASLD&#41; &#40;2011&#41;&#44; the European Molecular Genetics Quality Network &#40;EMQN&#41; &#40;2016&#41;&#44; and the American College of Gastroenterology &#40;ACG&#41; &#40;2019&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Genetic testing</span><p id="par0090" class="elsevierStylePara elsevierViewall">For the classic mutation of the HFE gene &#40;C282Y&#47;H63D&#41;&#46; The analysis was performed at our laboratory&#46; DNA was obtained from the sample in an automated manner on a QIAsymphony SP using the QIAsymphony DNA Midi kit QUIAGEN&#174;&#44; Werfen Group&#46; Subsequently&#44; the quantification of the DNA obtained was performed using QUAWELL UV SPECTROPHOTOMETER Q3000&#46; The study of C282Y&#47;H63D mutations of the hemochromatosis &#40;HFE&#41; gene&#44; LRG&#95;748t1 &#40;<a href="ncbi-n:NM_000410.3">NM&#95;000410&#46;3</a>&#41; &#40;NP&#95;000401&#46;1&#41;&#44; was carried out by RT-PCR &#40;Real Time PCR&#41; using the GenVinSet HFE-C282Y&#47;H63D kits &#40;ref&#46; GVS-H63D-48&#59; ref&#46; GVS-C282Y-48&#41;&#44; Blackhills Diagnostic Resources S&#46;L&#46;&#44; in the LightCycler 96 equipment &#40;Diagnostica Longwood&#41; using the LightCycler&#174; 96 v1&#46;1 software&#46; The detection method used is based on a PCR with specific primers for exon 2 &#40;His63Asp&#41; and exon 4 &#40;Cys282Tyr&#41; of the HFE gene and two Taqman&#174; probes specific for the normal gene and the mutated gene&#44; respectively&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">For those patients who underwent additional genetic studies&#44; non-HFE genes causing disease development &#40;<span class="elsevierStyleItalic">HFE2</span>&#44; <span class="elsevierStyleItalic">HAMP</span>&#44; <span class="elsevierStyleItalic">TFR2</span>&#44; <span class="elsevierStyleItalic">SLC40A1</span>&#44; <span class="elsevierStyleItalic">BMP6</span>&#41; were analysed in LABGENETICS&#44; Madrid-Spain&#46; DNA was obtained from the sample in an automated manner on a Maxwell&#174; 16 System using the Maxwell&#174; RSC Blood DNA kit &#40;Promega&#41;&#46; Subsequently&#44; the quantification of the DNA obtained by fluorimetry was performed using Qubit Fluorimetric Quantitation with the Qubit dsDNA BR Assay Kit&#46; For spot detection&#44; a haemochromatosis panel &#40;IAD188248&#41; was used for the preparation of libraries designed using Ion AmpliSeq&#8482; technology &#40;Thermo Fisher Scientific&#41;&#44; with a horizontal coverage of 100&#46;00&#37; of the coding region and 25<span class="elsevierStyleHsp" style=""></span>bp of the adjacent intronic regions of the 8 genes included in this panel&#44; with a size of 17&#46;74 Kb and comprising 66 amplicons&#46; For the preparation of libraries&#44; the Ion AmpliSeq&#8482; Library Kit 2&#46;0 was used&#46; Library quantification was performed in a 7500 Fast Real-Time PCR System from Applied Biosystems&#174;&#46; An emulsion and enrichment PCR was performed using the &#8220;Ion PGM&#8482; Hi-Q&#8482; View OT2 Kit&#8221; and &#8220;Ion PGM&#8482; Enrichment Beads&#8221; kits in an automated manner on an Ion OneTouch 2&#46;0 System&#46; Sequencing was performed on the Ion PGM System platform using the Ion PGM Hi-Q View Sequencing Kit on an Ion 316 Chip v2&#46; All potentially pathogenic SNVs and indels were validated by Sanger sequencing&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">For the analysis of large deletions&#47;duplications&#44; PCR amplification of different coding regions of the <span class="elsevierStyleItalic">HFE</span>&#44; <span class="elsevierStyleItalic">HFE2</span>&#44; <span class="elsevierStyleItalic">SLC40A1</span>&#44; <span class="elsevierStyleItalic">HAMP</span>&#44; and <span class="elsevierStyleItalic">TFR2</span> genes was performed using the MLPA technique with P347-A3 kits from the MRC-Netherlands&#46; The detection of the amplified products was performed by capillary electrophoresis under denaturing conditions in an Applied Biosystems&#174; 3500 DX Genetic Analyser&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Variants were named according to the <span class="elsevierStyleItalic">Human Genome Variation Society</span> &#40;HGVS&#41; recommendations &#40;<a href="http://varnomen.hgvs.org/">http&#58;&#47;&#47;varnomen&#46;hgvs&#46;org&#47;</a>&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Prevalence study</span><p id="par0110" class="elsevierStylePara elsevierViewall">Prevalence was calculated using the statistics software Microsoft&#174; Excel&#174; for Microsoft 365 MSO &#40;version 2306 build 16&#46;0&#46;16529&#46;20100&#41;&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">For prevalence calculation of HFE HC&#44; it was calculated the number of C282Y homozygous patients respect the total number of patients with suspected hemochromatosis who underwent genetic studies&#46; It was also calculated the number of C282Y homozygous patients respect the total population in Health Sector Zaragoza II&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">For prevalence calculation of non-HFE HC&#44; it was calculated the number of patients with non-HFE variants respect the total number of patients with suspected hemochromatosis who underwent genetic studies&#46; It was also calculated the number of patients with non-HFE variants respect the total population in Health Sector Zaragoza II&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Bioinformatic analysis</span><p id="par0125" class="elsevierStylePara elsevierViewall">The classification of the non-HFE variants was performed using the analysis software Alamut&#174; Visual 2&#46;15&#44; HGMD&#174; Professional 2017&#46;2&#44; gnomAD browser&#44; Varsome&#44; and ClinVar&#46; The reference sequences used to analyse the results were <span class="elsevierStyleItalic">BMP6</span> &#40;<a href="ncbi-n:NM_001718.5">NM&#95;001718&#46;5</a>&#41;&#44; <span class="elsevierStyleItalic">FTH1</span> &#40;<a href="ncbi-n:NM_002032.2">NM&#95;002032&#46;2</a>&#41;&#44; <span class="elsevierStyleItalic">FTL</span> &#40;<a href="ncbi-n:NM_000146.3">NM&#95;000146&#46;3</a>&#41;&#44; <span class="elsevierStyleItalic">HAMP</span> &#40;<a href="ncbi-n:NM_021175.2">NM&#95;021175&#46;2</a>&#41;&#44; <span class="elsevierStyleItalic">HFE</span> &#40;<a href="ncbi-n:NM_000410.3">NM&#95;000410&#46;3</a>&#41;&#44; <span class="elsevierStyleItalic">HFE2&#47;HJV</span> &#40;<a href="ncbi-n:NM_213653.3">NM&#95;213653&#46;3</a>&#41;&#44; <span class="elsevierStyleItalic">SLC40A1</span> &#40;<a href="ncbi-n:NM_014585.5">NM&#95;014585&#46;5</a>&#41;&#44; and <span class="elsevierStyleItalic">TFR2</span> &#40;<a href="ncbi-n:NM_003227.3">NM&#95;003227&#46;3</a>&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">All the variants found were classified according to the ACMG criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Clinical variables</span><p id="par0135" class="elsevierStylePara elsevierViewall">It was measured clinical events by using laboratory parameters of iron metabolism&#44; imaging test&#44; and treatment used &#40;phlebotomy and&#47;or electrophoresis&#41;&#46; Biochemical parameters&#58; ferritin&#44; TSI&#44; serum iron&#44; transferrin and C-reactive protein &#40;CRP&#41; were measured on an AU5800&#174; Chemistry System &#40;Beckman Coulter&#41;&#46; TSI was calculated as follows&#58; Ferritin<span class="elsevierStyleHsp" style=""></span>&#42;<span class="elsevierStyleHsp" style=""></span>100&#47;&#40;Transferrin<span class="elsevierStyleHsp" style=""></span>&#42;<span class="elsevierStyleHsp" style=""></span>1&#46;41&#41;&#46; Haematological parameters&#58; haemoglobin &#40;hb&#41;&#44; haematocrit &#40;ht&#41;&#44; and mean corpuscular volume &#40;MCV&#41; were measured on a DxH 900&#174; Haematology Analyser &#40;Beckman Coulter&#41;&#46; We took into account both magnetic resonance imaging &#40;MRI&#41; and laboratory results obtained just before genetic testing&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">It was registered the number of phlebotomies&#47;electrophoresis needed by each patient to normalized iron metabolism parameters and the total number of phlebotomies&#47;electrophoresis performed&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><p id="par0145" class="elsevierStylePara elsevierViewall">Health Sector of Zaragoza II corresponds to 377&#44;967 population&#46; One thousand five hundred forty-seven patients met the inclusion criteria proposed for the study&#46; Forty-seven patients underwent further studies on non-HFE genes&#46;</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Prevalence of HC</span><p id="par0150" class="elsevierStylePara elsevierViewall">The prevalence of HFE HC genetic confirmation &#40;C282Y homozygous&#41; respect the total of cases was 5&#46;95&#37; &#40;95 cases&#41;&#46; The prevalence of HFE HC genetic confirmation &#40;C282Y homozygous&#41; respect our population was 0&#46;025&#37;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">The prevalence of appearance of non-HFE HC variants respect the total of cases was 1&#46;94&#37; &#40;30 cases&#41;&#46; The prevalence of appearance of non-HFE HC variants respect our population was 0&#46;008&#37;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Prediction software results</span><p id="par0160" class="elsevierStylePara elsevierViewall">There were detected 27 non-classic HC variants&#46; Four variants in the HFE gene different from C282Y&#47;H63D classical mutation &#40;NM&#95;000410&#46;4 c&#46;1007-47G&#62;A&#44; NM&#95;000410&#46;4 c&#46;340&#43;4T&#62;C&#44; NM&#95;000410&#46;4 c&#46;82C&#62;T&#44; NM&#95;000410&#46;4 c&#46;892&#43;48G&#62;A&#41;&#46; And 23 variants in non-HFE genes &#40;<span class="elsevierStyleItalic">HJV</span>&#44; <span class="elsevierStyleItalic">HAMP</span>&#44; <span class="elsevierStyleItalic">TRF2</span>&#44; <span class="elsevierStyleItalic">SLC40A1</span>&#44; <span class="elsevierStyleItalic">BMP6</span>&#41; related to HC &#40;NM&#95;001718&#46;6 c&#46;1104G&#62;A&#44; NM&#95;001718&#46;6 c&#46;1281&#43;24T&#62;C&#44; NM&#95;001718&#46;6 c&#46;337C&#62;G&#44; NM&#95;001718&#46;6 c&#46;83G&#62;A&#44; NM&#95;001718&#46;6 c&#46;857&#43;12C&#62;T&#44; NM&#95;000146&#46;4 c&#46;163T&#62;C&#44; NM&#95;145277&#46;5 c&#46;335A&#62;T&#44; NM&#95;014585&#46;6 c&#46;&#42;1114T&#62;A&#44; NM&#95;014585&#46;6 c&#46;43&#43;68A&#62;C&#44; NM&#95;014585&#46;6 c&#46;44-24G&#62;C&#44; NM&#95;014585&#46;6 c&#46;533G&#62;A&#44; NM&#95;014585&#46;6 c&#46;663T&#62;C&#44; NM&#95;014585&#46;6 c&#46;-8C&#62;G&#44; NM&#95;014585&#46;6 c&#46;-98G&#62;C&#44; NM&#95;003227&#46;4 c&#46;1270&#43;16A&#62;G&#44; NM&#95;003227&#46;4 c&#46;1364G&#62;A&#44; NM&#95;003227&#46;4 c&#46;1851C&#62;T&#44; NM&#95;003227&#46;4 c&#46;1995&#43;9G&#62;C&#44; NM&#95;003227&#46;4 c&#46;2101C&#62;T&#44; NM&#95;003227&#46;4 c&#46;2255G&#62;A&#44; NM&#95;003227&#46;4 c&#46;2278G&#62;A&#44; NM&#95;003227&#46;4 c&#46;2343G&#62;A&#44; NM&#95;003227&#46;4 c&#46;64G&#62;A&#41;&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">According to the ACMG criteria&#44; the variants NM&#95;000410&#46;4 c&#46;82C&#62;T&#44; NM&#95;145277&#46;5 c&#46;335A&#62;T&#44; and NM&#95;014585&#46;6 c&#46;&#42;1114T&#62;A were characterised as uncertain significance&#46; In addition&#44; the variants NM&#95;014585&#46;6 c&#46;533G&#62;A&#44; NM&#95;003227&#46;4 c&#46;2101C&#62;T and NM&#95;003227&#46;4 c&#46;2343G&#62;A were characterised as pathogenic&#47;likely pathogenic &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Deletereus effect on the protein of the pathogenic&#47;likely pathogenic and uncertain significant variants</span><p id="par0170" class="elsevierStylePara elsevierViewall">The NM&#95;000410&#46;4 c&#46;82C&#62;T variant is a missense variant &#40;CADD score 24&#46;6&#41;&#44; which generated an abnormal HFE protein in which amino acid 28 histidine has been replaced by tyrosine&#46; This change affects a highly conserved region of the HFE protein&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">The NM&#95;145277&#46;5 c&#46;335A&#62;T variant is a missense variant &#40;CADD score 28&#46;3&#41;&#44; which causes an abnormal HJV protein in which amino acid 112 lysine has been replaced by methionine&#46; This change affects a highly conserved region of the HJV protein&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">The NM&#95;014585&#46;6 c&#46;&#42;1114T&#62;A variant is located at the 3&#8242;UTR region in the 8 exon&#44; position 1428 of 1602&#44; is located in the exon 8 of the gene&#44; it affect a non-coding region but the effect on the SLC40A1 protein generated is yet unknown&#44; as it can possibly affect a highly conserved region of the SLC40A1 protein&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">The NM&#95;014585&#46;6 c&#46;533G&#62;A variant is a missense variant &#40;CADD score 30&#41;&#44; which causes an abnormal SLC40A1 protein in which amino acid 178 arginine has been replaced by glycine&#46; This change affects a highly conserved region of the SLC40A1 protein&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">The NM&#95;003227&#46;4 c&#46;2101C&#62;T variant is a nonsense variant&#44; in which codon 701 that codified for amino acid arginine is substituted by a termination codon&#46; This originates a truncated protein of 700 amino acid compared to 801 of the normal one&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">The NM&#95;003227&#46;4 c&#46;2343G&#62;A variant is a nonsense variant&#44; in which codon 781 that codified for amino acid tryptophan is substituted by a termination codon&#46; This originates a truncated protein of 700 amino acid compared to 801 of the normal one&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Genotype and clinical characteristics of patients with pathogenic&#47;likely pathogenic and uncertain significant variants</span><p id="par0200" class="elsevierStylePara elsevierViewall">The NM&#95;000410&#46;4 c&#46;82C&#62;T variant was detected in a patient &#40;HC21&#41; with high serum ferritin levels &#40;523&#46;50<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; normal range&#58; 15&#8211;200<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41;&#44; but TSI and serum iron were within the normal range&#46; She did not present any other clinical signs of iron overload&#44; and did not need to be treated with phlebotomies&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">The NM&#95;145277&#46;5 c&#46;335A&#62;T variant was detected in heterozygosity in a patient &#40;HC10&#41; in which the MRI revealed a moderate hepatic iron overload of 25&#46;60<span class="elsevierStyleHsp" style=""></span>&#956;Fe&#47;G&#46; Currently&#44; she is in treatment with phlebotomies&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">The NM&#95;014585&#46;6 c&#46;&#42;1114T&#62;A variant was detected in heterozygosity in a patient &#40;HC1&#41; who presented altered iron metabolism parameters&#58; ferritin 2426 ng&#47;mL and TSI 54&#46;72&#37; &#40;20&#8211;40&#37;&#41;&#44; in addition to a moderate hepatic iron overload seen on MRI&#46; He needed 43 phlebotomies to normalize iron metabolism parameters&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">The NM&#95;014585&#46;6 c&#46;533G&#62;A variant was detected in heterozygosity in a patient &#40;HC4&#41; with altered ferritin levels &#40;1098<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; but normal TSI and serum iron levels&#46; MRI also showed no iron hepatic overload&#46; Even after treatment with phlebotomies&#44; he received 13 in total&#44; iron metabolism parameters did not normalize&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">The NM&#95;003227&#46;4 c&#46;2101C&#62;T and the NM&#95;003227&#46;4 c&#46;2343G&#62;A variants were detected in heterozygosity in a patient &#40;HC24&#41; who presented altered levels of ferritin &#40;2109&#46;10<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41;&#44; TSI &#40;86&#46;59&#37;&#41; and serum iron &#40;203&#46;00<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;dL&#44; normal range&#58; 60&#8211;180<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;dL&#41;&#46; MRI also showed hepatic iron overload&#46; He is in treatment with phlebotomies&#44; but after receiving 13&#44; iron metabolism parameters still have not normalized&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">The NM&#95;003227&#46;4 c&#46;2343G&#62;A variant was also detected in homozygosity in a patient &#40;HC15&#41; with long-standing hypersideremia who was diagnosed at the age of 29 with HC&#46; She has been in treatment with phlebotomies since 1999&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Genotype characterization and clinical featured of all patient mentioned above are summarised at the following tables &#40;<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Discussion</span><p id="par0235" class="elsevierStylePara elsevierViewall">As other studies before&#44;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">18&#8211;20</span></a> the present study shows that the prevalence of HFE HC is lower in our population than in the North European population&#46; Seventy-six percent of cases diagnosed with HC correspond to HFE haemochromatosis and the remaining 24&#37; are due to variants in other non-HFE genes&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Specifically&#44; the prevalence of C282Y homozygotes in patients with symptoms of iron overload was 5&#46;95&#37;&#44; a result slightly lower to that obtained by Gomez-Llorente et al&#46; in their study in which 6&#46;13&#37; of subjects with abnormal iron metabolism were homozygous for the HFE C282Y variant&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">20</span></a> probably explained by our larger sample size &#40;1547 patients compared to 359&#41;&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">On the other hand&#44; Wallace et al&#46; provide a global prevalence of HFE and specially non-HFE hemochromatosis through pathogenic allele frequencies data&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">1</span></a> In our case&#44; we estimated the prevalence of the appearance of non-HFE variants in both the general population&#44; 0&#46;008&#37;&#44; and patients with symptoms of iron overload&#44; 1&#46;94&#37;&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">It should be taken into account that only 3&#46;17&#37; of the patients initially studied for the C282Y&#47;H63D mutations underwent further non-HFE studies&#46; Due to clinical practice&#44; not all patient with a negative result on C282Y&#47;H63D mutations underwent further non-HFE studies&#46; The study period is too long&#44; and the genetic diagnosis of HC has been changing as there were found new genes causing the disease&#46; This has led to the progressive reevaluation of some patients and the adaptation of hospital protocols to the latest clinical practice guidelines&#46; This contributes to a heterogeneity of the genetic results obtained over the years and constitutes the main limitation of our work since the real prevalence of non-HFE variants could be misestimate&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">When analysing patients with a non-HFE variants and clinical manifestations of iron overload&#44; it is surprising that only six patients &#40;20&#37; of the cases&#41; presented any pathogenic&#47;probably pathogenic or uncertain significance variant&#46; Besides&#44; only in three of them &#40;10&#37; of the cases&#41; these variants found could explain the symptoms&#46; The rest &#40;27 cases&#41; remain without genetic justification for their hyperferritinemia&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">In one hand we have&#44; patient HC4 that presents the variant NM&#95;014585&#46;6 c&#46;533G&#62;A classified as pathogenic&#46; Chandran et al&#46; have previously described this variant in several patients who&#44; like ours&#44; present elevated ferritin levels but normal TSI levels&#46; In their study&#44; a new pathogenic mechanism was proposed&#46; The presence of the NP&#95;055400&#46;1 p&#46;Arg178Gln mutated protein reduces the ability of FPN1 to export iron without causing protein mislocalization&#46; The amino acid p&#46;Arg178 would be part of an interaction network modulating the conformational changes required for iron transport&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">8</span></a> The presence of this mutation in heterozygosis is compatible with ferroportin diseases or HC type 4A and justified the clinical manifestation of our patient&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Patient HC15 which presented in homozygosis the previously reported NM&#95;003227&#46;4 c&#46;2343G&#62;A variant&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">21</span></a> In Bardou-Jaquet et al&#46; case the NM&#95;003227&#46;4 c&#46;2343G&#62;A was presented in compound heterozygosis with another TFR2 variant &#40;p&#46;Arg730Cys&#41; in a patient with early onset HC type 3&#44; as in our case before the age of 30&#46; In a subsequent genetic study carried out on both parents&#44; it was found that they present the same variant in heterozygosis&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">In addition&#44; patient HC 24 also presented the NM&#95;003227&#46;4 c&#46;2343G&#62;A variant in compound heterozygosis with the pathogenic variant NM&#95;003227&#46;4 c&#46;2101C&#62;T&#46; The NM&#95;003227&#46;4 c&#46;2101C&#62;T variant has been previously describe<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">22</span></a> in a patient with similar characteristics and the presence of the mutation in homozygosis&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Both variant NM&#95;003227&#46;4 c&#46;2343G&#62;A&#46; and NM&#95;003227&#46;4 c&#46;2101C&#62;T originated respectively the truncated proteins NP&#95;003218&#46;2 p&#46;Trp781Ter and NP&#95;003218&#46;2 p&#46;Arg701Ter&#46; located at the TFR dimeric domain&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">22&#44;23</span></a> TFR 2 dimerization is an essential step for its normal activity&#44; the presence of a truncated protein at this level would affect the interaction TFR2&#47;Tf&#44; reducing the signalling cascade for hepcidine production&#44; and&#44; at the end&#44; iron accumulation&#46; Our cases confirm HC type 3 presents with more severe and earlier iron overload complications compared with type 1 and 4b&#44; as it was already reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">21&#44;24&#44;25</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">On the other hand&#44; we have the case of patient HC1 who presented the uncertain significance variant &#40;VUS&#41; NM&#95;014585&#46;6 c&#46;&#42;1114T&#62;A&#46; This variant has a low allele frequency &#40;0&#46;001971&#37;&#41;&#44; and the results of various prediction algorithms suggest that the protein generated may cause disease&#46; However&#44; in the predictive study of relatives&#44; it was found that a brother and both children of the proband had the same mutation&#46; The all three were asymptomatic&#46; If they develop symptoms of the disease&#44; it would support the diagnosis of HC type 4&#44; and the reclassification of the variant from VUS to possibly pathogenic&#46; Nevertheless&#44; for the moment until more evidence remains without a clear genetic diagnosis&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">Moreover&#44; both patient HC10 and HC21 presented a VUS &#40;NM&#95;145277&#46;5 c&#46;335A&#62;T in the case of patient HC10&#44; and NM&#95;000410&#46;4 c&#46;82C&#62;T in the case of patient HC21&#41;&#46; In both cases&#44; even in the event that those variants were a pathogenic mutation&#44; since the mode of inheritance of type 1 and type 2 Hemochromatosis is autosomal recessive&#44; the presence of a single mutation would not be diagnostic for the development of the disease&#46; However&#44; as the patients presented symptoms associated with haemochromatosis&#44; it is possible that they present another variants not yet identify&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">A new type of hemochromatosis has recently been included in OMIM&#46; Hemochromatosis type 5 &#40;OMIM&#35; 615517&#41; is caused by heterozygous mutation in the <span class="elsevierStyleItalic">FTH1</span> gene &#40;134770&#41; on chromosome 11q12&#46; The <span class="elsevierStyleItalic">FTH1</span> gene codifies the synthesis of the heavy chain subunit &#40;FTH&#41; of the ferritin&#46; The FTH has the ferroxidase activity centre while the light chain subunit &#40;FTL&#41; is responsible of the iron-storage function of the ferritin&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">26</span></a> A mutation in the <span class="elsevierStyleItalic">FTH1</span> gene was studied in a Japanese family in which the proband presented high serum ferritin level&#44; as well as an increase in both serum iron and transferrin saturation&#46; Iron deposition in liver&#44; heart&#44; and bone marrow shown on MRI and on liver&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">27</span></a> This opens the door to the reassessment of those patients still without a clear molecular diagnosis&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conclusion</span><p id="par0295" class="elsevierStylePara elsevierViewall">We can affirm that the prevalence of CH in our population is similar to that found in geographically close areas&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">Second-level genetic tests &#40;NGS and MLPA&#41; help in clinical practice the study of non-HFE HC cases&#44; allowing us to find a molecular cause of iron overload&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">However&#44; we count with large number of patients who present some polymorphism in genes associated to hepcidin synthesis pathway&#47;iron metabolism routes&#44; which even today remain without finding a molecular cause to their iron overload symptoms&#46; For this reason&#44; it is important to perform periodic reassessments of these patients in our clinical practice&#46; Just as important as to review what new genes could be involved in the pathogenesis of the disease&#46; As clinicians&#44; we cannot forget that the final objective is not only to provide a molecular&#47;metabolic justification to our patient but also to provide them with a clinical diagnosis of their disease&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Ethical considerations</span><p id="par0310" class="elsevierStylePara elsevierViewall">This study was performed in accordance with the Declaration of Helsinki and it was approved by the committee of health care ethics in Aragon &#40;CEICA&#41; with number PI20&#47;397&#46; Informed consent was obtained from participants before performing the genetic study&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Funding</span><p id="par0315" class="elsevierStylePara elsevierViewall">This research did not receive any specific grant from funding agencies in the public&#44; commercial&#44; or not-for-profit sectors&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Authors&#8217; contributions</span><p id="par0320" class="elsevierStylePara elsevierViewall">CAM&#58; conception and design of the study&#44; acquisition of data&#44; analysis and&#47;or interpretation of data and drafting the manuscript and revising the manuscript for important intellectual content&#46; NGR&#58; analysis and&#47;or interpretation of data and drafting the manuscript&#46; RGT&#58; analysis and&#47;or interpretation of data and revising the manuscript for important intellectual content&#46; LRV&#58; analysis and&#47;or interpretation of data and revising the manuscript for important intellectual content&#46; VRF&#58; conception and design of the study&#44; acquisition of data&#44; and revising the manuscript for important intellectual content&#46; SIA&#58; conception and design of the study&#44; analysis and&#47;or interpretation of data and revising the manuscript for important intellectual content&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">All authors revised and approved the manuscript final version&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conflict of interest</span><p id="par0330" class="elsevierStylePara elsevierViewall">The authors declare that they have not conflict of interest&#46;</p></span></span>"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Genetic testing"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Prevalence study"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Bioinformatic analysis"
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            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Clinical variables"
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        6 => array:3 [
          "identificador" => "sec0040"
          "titulo" => "Results"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Prevalence of HC"
            ]
            1 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Prediction software results"
            ]
            2 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Deletereus effect on the protein of the pathogenic&#47;likely pathogenic and uncertain significant variants"
            ]
            3 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Genotype and clinical characteristics of patients with pathogenic&#47;likely pathogenic and uncertain significant variants"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Discussion"
        ]
        8 => array:2 [
          "identificador" => "sec0070"
          "titulo" => "Conclusion"
        ]
        9 => array:2 [
          "identificador" => "sec0075"
          "titulo" => "Ethical considerations"
        ]
        10 => array:2 [
          "identificador" => "sec0080"
          "titulo" => "Funding"
        ]
        11 => array:2 [
          "identificador" => "sec0085"
          "titulo" => "Authors&#8217; contributions"
        ]
        12 => array:2 [
          "identificador" => "sec0090"
          "titulo" => "Conflict of interest"
        ]
        13 => array:2 [
          "identificador" => "xack759033"
          "titulo" => "Acknowledgements"
        ]
        14 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2024-02-01"
    "fechaAceptado" => "2024-05-13"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1848105"
          "palabras" => array:5 [
            0 => "Haemochromatosis"
            1 => "Iron overload"
            2 => "Hyperferritinemia"
            3 => "Next-generation sequencing"
            4 => "Multiplex ligation-dependent probe amplification"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1848104"
          "palabras" => array:5 [
            0 => "Hemocromatosis"
            1 => "Sobrecarga de hierro"
            2 => "Hiperferritinemia"
            3 => "<span class="elsevierStyleItalic">Next-generation sequencing</span>"
            4 => "<span class="elsevierStyleItalic">Multiplex ligation-dependent probe amplification</span>"
          ]
        ]
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    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The main genetic cause of iron overload is haemochromatosis &#40;HC&#41;&#46; In recent years&#44; the study of non-HFE genes &#40;<span class="elsevierStyleItalic">HFE2</span>&#44; <span class="elsevierStyleItalic">HJV</span>&#44; <span class="elsevierStyleItalic">HAMP</span>&#44; <span class="elsevierStyleItalic">TRF2</span>&#44; <span class="elsevierStyleItalic">SLC40A1</span>&#44; and <span class="elsevierStyleItalic">BMP6</span>&#41; has become relevant thanks to next-generation sequencing &#40;NGS&#41; and multiplex ligation-dependent probe amplification &#40;MLPA&#41; techniques&#46; Our objectives were to estimate the prevalence of both HFE &#40;C282Y&#47;HY63D variants&#41; and non-HFE variants attending a tertiary hospital in Arag&#243;n&#44; to predict the effect of the variants on the protein&#44; and to establish a genotype&#8211;phenotype correlation evaluating with the clinical context&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Retrospective descriptive study from 2006 to 2020 of patients attended at genetic consultation in a reference hospital for HC in Aragon&#46; We calculated prevalence of HFE and non-HFE variants&#46; We analysed non-HFE genes &#40;<span class="elsevierStyleItalic">HFE2</span>&#44; <span class="elsevierStyleItalic">HJV</span>&#44; <span class="elsevierStyleItalic">HAMP</span>&#44; <span class="elsevierStyleItalic">TRF2</span>&#44; <span class="elsevierStyleItalic">SLC40A1</span>&#44; and <span class="elsevierStyleItalic">BMP6</span>&#41;&#44; used bioinformatics tools&#44; consulted different databases and measured clinical parameters &#40;laboratory and imaging&#41;&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The prevalence of C282Y homozygous was 5&#46;95&#37; respect the total of cases and 0&#46;025&#37; respect our population&#46; The prevalence of non-HFE HC variants was 1&#46;94&#37; respect the total of cases and 0&#46;008&#37; respect our population&#46; We found 27 variants in non-<span class="elsevierStyleItalic">HFE</span> genes and 4 in <span class="elsevierStyleItalic">HFE</span> gene&#44; of which 6 were classified as variant of uncertain clinical significance &#40;VUS&#41;&#44; or likely pathogenic or pathogenic according to the ACMG classification criteria&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Our prevalence results are as expected&#44; and similar to those obtained by other studies&#46; Although some of the genetic findings explain the clinical symptoms of some of our patients&#44; we remain have a high number of patients without a clear molecular diagnosis&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusion"
          ]
        ]
      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La principal causa gen&#233;tica de sobrecarga de hierro es la hemocromatosis&#46; En los &#250;ltimos a&#241;os ha ganado importancia el estudio de los genes no-HFE &#40;<span class="elsevierStyleItalic">HFE2</span>&#44; <span class="elsevierStyleItalic">HJV</span>&#44; <span class="elsevierStyleItalic">HAMP</span>&#44; <span class="elsevierStyleItalic">TRF2</span>&#44; <span class="elsevierStyleItalic">SLC40A1</span> y <span class="elsevierStyleItalic">BMP6</span>&#41; gracias a las t&#233;cnicas <span class="elsevierStyleItalic">next-generation sequencing</span> &#40;NGS&#41; y <span class="elsevierStyleItalic">multiplex ligation-dependent probe amplification</span> &#40;MLPA&#41;&#46; Nuestros objetivos son estimar la prevalencia de las variantes HFE &#40;C282Y&#47;HY63D&#41; y no-HFE en nuestro hospital&#44; predecir el efecto de las variantes en la prote&#237;na y establecer una correlaci&#243;n genotipo-fenotipo evaluando con el contesto cl&#237;nico&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Metodolog&#237;a</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio descriptivo retrospectivo desde 2006 a 2020 de pacientes que asistieron a consulta de gen&#233;tica en un hospital terciario en Arag&#243;n&#46; Calculamos la prevalencia de las variantes HFE y no-HFE&#46; Analizamos los genes no-HFE &#40;<span class="elsevierStyleItalic">HFE2</span>&#44; <span class="elsevierStyleItalic">HJV</span>&#44; <span class="elsevierStyleItalic">HAMP</span>&#44; <span class="elsevierStyleItalic">TRF2</span>&#44; <span class="elsevierStyleItalic">SLC40A1</span> y <span class="elsevierStyleItalic">BMP6</span>&#41; usando herramientas bioinform&#225;ticas&#44; consultando diferentes bases de datos y midiendo par&#225;metros cl&#237;nicos &#40;laboratorio e imagen&#41;&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La prevalencia de homocigotos C282Y fue del 5&#44;95&#37; respecto del total de casos y del 0&#44;025&#37; respecto de la poblaci&#243;n en Arag&#243;n&#46; La prevalencia de variantes no-HFE fue del 1&#44;94&#37; respecto al total de casos y del 0&#44;008&#37; respecto de la poblaci&#243;n en Arag&#243;n&#46; Encontramos 27 variantes en genes no-HFE y 4 en genes HFE&#44; de las cuales 6 fueron clasificadas como de significado incierto&#44; como probablemente patog&#233;nicas o como patog&#233;nicas seg&#250;n los criterios de clasificaci&#243;n de la ACMG&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Nuestros resultados de prevalencia fueron los esperados y similares a aquellos obtenidos en otros estudios&#46; Aunque algunos de los hallazgos gen&#233;ticos explican los s&#237;ntomas cl&#237;nicos de algunos de nuestros pacientes&#44; seguimos teniendo un elevado n&#250;mero de pacientes sin un diagn&#243;stico molecular claro&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Antecedentes"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Metodolog&#237;a"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusi&#243;n"
          ]
        ]
      ]
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            "identificador" => "at1"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Transcript&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Coding impact&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Allele frequency&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ACMG classification&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Classifying criteria&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleInterRef" id="intr0005" href="ncbi-n:NM_000410.4">NM&#95;000410&#46;4</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">c&#46;82C&#62;T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Missense &#40;CADD score 24&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;000657&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Uncertain significance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">PP3&#47;PM1&#47;PM2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">HJV</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleInterRef" id="intr0010" href="ncbi-n:NM_145277.5">NM&#95;145277&#46;5</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">c&#46;335A&#62;T&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Missense &#40;CADD score 28&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">PM2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">SLC40A1</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleInterRef" id="intr0015" href="ncbi-n:NM_014585.6">NM&#95;014585&#46;6</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">c&#46;&#42;1114T&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">rs1255810280&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;001971&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">PM2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleInterRef" id="intr0020" href="ncbi-n:NM_014585.6">NM&#95;014585&#46;6</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">c&#46;533G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">rs1449300685&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Missense &#40;CADD score 30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Not found&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PS3&#47;PP3&#47;PP5&#47;PM1&#47;PM2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleInterRef" id="intr0025" href="ncbi-n:NM_003227.4">NM&#95;003227&#46;4</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;2101C&#62;T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">rs946552921&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nonsense&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;003942&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PVS1&#47;PP5&#47;PM2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TFR2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleInterRef" id="intr0030" href="ncbi-n:NM_003227.4">NM&#95;003227&#46;4</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;2343G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">rs768907730&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nonsense&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;003284&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Likely pathogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PVS1&#47;PP5&#47;PM2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case number&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Genotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ACMG classification&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HH1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SLC40A1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;014585&#46;6 c&#46;&#42;1114T&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Uncertain significance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HH4<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#8224;</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SLC40A1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;014585&#46;6 c&#46;533G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TFR2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;003227&#46;4 c&#46;1364G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Likely benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TFR2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;003227&#46;4 c&#46;1995&#43;9G&#62;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Likely benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HH10</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SLC40A1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;014585&#46;6 c&#46;44-24G&#62;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">HJV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;145277&#46;5 c&#46;335A&#62;T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Uncertain significance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HH15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TFR2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;003227&#46;4 c&#46;2343G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Homozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Likely pathogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HH21</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SLC40A1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;014585&#46;6 c&#46;44-24G&#62;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SLC40A1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;014585&#46;6 c&#46;-8C&#62;G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SLC40A1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;014585&#46;6 c&#46;-98G&#62;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">HFE</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;000410&#46;4 c&#46;82C&#62;T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Uncertain significance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">FTL</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;000146&#46;4 c&#46;163T&#62;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Homozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HH24</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SLC40A1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;014585&#46;6 c&#46;44-24G&#62;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Homozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SLC40A1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;014585&#46;6 c&#46;43&#43;68A&#62;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SLC40A1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;014585&#46;6 c&#46;-8C&#62;G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SLC40A1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;014585&#46;6 c&#46;-98G&#62;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">BMP6</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;001718&#46;6 c&#46;337C&#62;G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">BMP6</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;001718&#46;6 c&#46;1104G&#62;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Likely benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">BMP6</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;001718&#46;6 c&#46;1281&#43;24T&#62;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Homozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">HFE</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;000410&#46;4 c&#46;340&#43;4T&#62;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">HFE</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;000410&#46;4 c&#46;1007-47G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TFR2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;003227&#46;4 c&#46;2343G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Likely pathogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TFR2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;003227&#46;4 c&#46;2101C&#62;T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TFR2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;003227&#46;4 c&#46;1851C&#62;T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heterozygous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">FTL</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NM&#95;000146&#46;4 c&#46;163T&#62;C&nbsp;\t\t\t\t\t\t\n
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                  """
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                        "fecha" => "2001"
                        "volumen" => "69"
                        "paginaInicial" => "191"
                        "paginaFinal" => "197"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11389486"
                            "web" => "Medline"
                          ]
                        ]
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                    ]
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              ]
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    "agradecimientos" => array:1 [
      0 => array:4 [
        "identificador" => "xack759033"
        "titulo" => "Acknowledgements"
        "texto" => "<p id="par0335" class="elsevierStylePara elsevierViewall">We would like to thank Blackhills Diagnostic Resources S&#46;L&#46;U&#46; &#40;BDR&#41;&#44; Zaragoza&#44; Spain&#46;</p>"
        "vista" => "all"
      ]
    ]
  ]
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