Clinical report
Triplet expansion cytosine–guanine–guanine: Three cases of OMIM syndrome in the same family
Expansión del triplete citosina-guanina-guanina: 3 casos de síndrome OMIM en una misma familia
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III 1, III: 2; III: 3: FXPOI; II:1: FXTAS; IV:4: asymptomatic premutation/full mutation mosaic.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Fragile X syndrome (FXS) is one of the most common inherited cause of intellectual disability, it is an inherited X-linked dominant disorder with reduced penetrance, which affects approximately 1/3500 to 9000 males.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a> Usually women are carriers in a 3:1 ratio compared to men, but can also be affected, with a prevalence of half the rate compared to men.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a> The patient's clinical profile begins with psychomotor impairment, primarily of language, which later proves to be a (mild to severe) intellectual disability along with the variable associations of other disorders, among which include attention-deficit/hyperactivity disorder, autism, language and learning impairment and characteristic phenotypic traits (long face, broad forehead, prominent chin, large and detached ears).<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">2–5</span></a> The dynamic genetic mutation, an increase in the number of repeats of cytosine–guanine–guanine (CGG) in the <span class="elsevierStyleItalic">Fragile X Mental Retardation 1 (FMR1)</span> gene (<a id="intr0010" class="elsevierStyleInterRef" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=nucleotide&doptcmdl=genbank&term=NM_002024.5">NM_002024.5</a>), is responsible for three OMIM syndromes with distinct clinical phenotype<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">6</span></a>: FXS (# MIM300624); and two diseases in adult carriers of the premutation of the <span class="elsevierStyleItalic">FMR1</span> gene (55–200 CGG repeats): primary ovarian insufficiency (FXPOI) (# MIM311360) and tremor–ataxia associated with SFX (FXTAS) (# MIM300623).<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">7–9</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Cases of FXS, FXPOI and FXTAS found in the same family is presented, showing the importance of the implementation of new diagnostic methodologies in the study of dynamics mutation in the FMR1 gene, such as the triplet repeat first-polymerase chain reaction (PT-PCR) for early diagnosis.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Clinical observation or methods</span><p id="par0015" class="elsevierStylePara elsevierViewall">A number of cases, from the same family, of patients suffering FXS–some premutation carriers with associated clinical symptoms–FXPOI and FXTAS are presented. FXS diagnosis in the index case was made initially through a conventional PCR technique in 2005, obtaining a negative result. Subsequently, the CGG dynamic mutation of the <span class="elsevierStyleItalic">FMR1</span> gene was studied in samples of deoxyribonucleic acid of the index case peripheral blood (reassessment) and other first, second and third degree relatives by TP-PCR, with the AmplideX<span class="elsevierStyleSup">®</span> FMR1 PCR kit reagents with CGG repeat primed PCR, and the percentage of methylation by AmplideX FMR1 mPCR (Asuragen<span class="elsevierStyleSup">®</span>) in an ABI<span class="elsevierStyleSup">®</span> 3130xl sequencer and using the GeneMapper<span class="elsevierStyleSup">®</span> 4.0 software. Patients were considered to have full mutation if they have more than 200 CGG repeats in the <span class="elsevierStyleItalic">FMR1</span> gene located at the FRAXA site in the Xq27.3 region. The patients’ also present the methylated gene (inactive) and absence of the Fragile X Mental Retardation Protein (FMRP protein).<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">10</span></a> Patients are classified as having premutations if they possess between 55 and 200 CGG triplet repeats.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">10</span></a> Normal subjects are those that have a polymorphism of between 5 and 54 triplet repeats without the production of the final protein being altered. Normal allele <span class="elsevierStyleMonospace"><</span>45 CGG repeats; intermediate allele 45–54 CGG repeats; premutation allele 55–200 CGG repeats; full mutated allele >200 CGG repeats.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">10–12</span></a> The adenine–guanine–guanine (AGG) interruptions was analysed in premutation patients in order to assess the risk of CGG triplet expansion in later generations, especially in women at gestational age.<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">13–16</span></a> The physical description, clinical and genetic study of the patients comprising the study was recorded.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Index case</span><p id="par0020" class="elsevierStylePara elsevierViewall">A 2-year-old boy, from a premature birth at 34 weeks of gestational age and new-born weight of 1165<span class="elsevierStyleHsp" style=""></span>g, referred to the Neuropediatrics clinic because of psychomotor impairment, learning difficulties and peculiar phenotype: microcephaly, elongated face, broad forehead, large and detached ears. First diagnostic tests included a complete blood count, biochemical analysis (liver and kidney function and metabolic), ophthalmologic study, baseline electroencephalogram, transfontanelar ultrasound, high-resolution karyotype and FXS study, all obtaining results within the limits of normality. He was monitored, identifying a significant development of backwardness, intellectual disabilities and attention deficit hyperactivity disorder. A brain MRI was conducted in which no findings were obtained and the genetic study of subtelomeric regions obtained negative results; but the molecular karyotyping, array comparative genomic hybridisation (CGH) where a 1q21.1 microdeletion and segmental monosomy of ∼1.35<span class="elsevierStyleHsp" style=""></span>Mb located on the long arm of chromosome 1 were detected which could justify the patient's intellectual disability. Based on the patient's phenotype, despite the finding in the array CGH, FXS was re-evaluated by a new technique implemented in the laboratory (TP-PCR Asuragen<span class="elsevierStyleSup">®</span>) obtaining <span class="elsevierStyleMonospace">></span>200 CGG repeats, confirming FXS. This finding showed the false negative with the conventional PCR technique that was initially used.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Study of the family</span><p id="par0025" class="elsevierStylePara elsevierViewall">Following the discovery of FXS in the index case, a family study was initiated to detect possible cases that may be undiagnosed or misdiagnosed and to offer appropriate genetic counselling.</p><p id="par0030" class="elsevierStylePara elsevierViewall">A total of 14 patients (including the index case) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), of whom 50% were male were studied. A diagnosis of FXS in 3 patients (21.4%) was confirmed, 8 patients (57.1%) were premutation, a male patient had premutation/full-mutation mosaicism (7.1%) and 2 patients (14.3%) had a CGG repeats number in the normal range (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Patients affected with FXS were diagnosed in childhood. In the three patients, the phenotypical features that stood out were their large and detached ears, elongated faces and that they all had intellectual disabilities to a greater or lesser degree as well as attention deficit hyperactivity disorder.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,5</span></a> Of the eight premutation patients, 50% had syndromes associated with fragile X syndrome (three cases of FXPOI and one case of FXTAS).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0035" class="elsevierStylePara elsevierViewall">Our series of cases identified three OMIM syndromes related to the expansion of CGG triplets in one single family: FXS, FXTAS and FXPOI. The index case reported presents two genetic alterations (deletion in the 1q21.1 chromosome and full mutation of FXS), that we describe for the first time in the literature associated in the same patient as probable causes of presenting clinical intellectual disability, attention deficit, a phenotype compatible with FXS and microcephaly.</p><p id="par0040" class="elsevierStylePara elsevierViewall">A genetic study of FXS is included in the different protocols established for the study of children with cognitive and psychomotor impairment. A karyotype and FXS is performed on children with a cognitive impairment and/or intellectual disability, and if these are negative, the array CGH is performed. In the index case the array CGH detected a segmental monosomy of ∼1.35<span class="elsevierStyleHsp" style=""></span>Mb on the long arm of chromosome 1 (1q21.1), described in the literature as a cause of mild to moderate intellectual impairment, cataracts, heart disease and diverse phenotype in which microcephaly is predominant.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">17</span></a> Despite having this aetiologic diagnosis and because there were such suggestive phenotypic characteristics, a new FXS study was performed using a new technique implemented in the laboratory (TP-PCR, Asuragen<span class="elsevierStyleSup">®</span>) which confirmed a full mutation and the condition and transmitter of FXS.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The deletion of 1.35<span class="elsevierStyleHsp" style=""></span>Mb in chromosome 1q21.1 (# MIM612474) added to the full mutation of FXS not having been reported previously in the same patient, as the interpretation and allocation of different clinical cases to each one of the genetic alterations was complex. This case highlights the difficulty of the aetiologic diagnosis in cases of intellectual disability as well as the importance of achieving as much as we can from genetic studies within our reach because of the subsequent impacts (genetic counselling) that may be involved.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The existence of premutation of the <span class="elsevierStyleItalic">FMR1</span> gene in the general population is relatively common<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">18</span></a> (1:130–250 women, 1:800 men) and in regard to this state, clinical cases have been identified such as FXTAS,<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">6,7</span></a> which can be seen in up to 20% of adult, male, premutation patients aged between 50 and 60 years-old, and FXPOI,<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">6,7</span></a> causing early menopause in up to 15–20% of premutation women compared to 1% of the general population. In our case series, of the eight premutation patients, 50% had syndromes related to FXS: three patients had FXPOI and one male patient had FXTAS. In turn, a tendency to early menopause was observed as the mother of the index case (case iii:7) presented amenorrhoea at age 44. The number of repeats has been correlated with the risk of developing FXPOI, where women with one allele of 80–100 CGG repeats increased risk of FXPOI<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">6</span></a> and those with <span class="elsevierStyleMonospace">></span>100 CGG repeats have shown no differences compared to the general population. The three patients diagnosed with FXPOI in our study had an allele in the range of range 80–100 CGG repeats. Note that apart from developing FXPOI or FXTAS, premutation adults are predisposed to mood changes, depression and difficulties in socialising as in the case iv:1.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">19</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Premutation expansion correlates with size, being greater the higher the number of CGG repeats in the mother and the fewer interruptions AGG presents.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">13</span></a> Recent studies have presented the possibility that the detection of AGG interruptions can predict genomic stability, and its presence is a protective factor in premutations in ranges of 80–90 repeats, so that no expansion of CGG triplets occur in descendants.<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">13–16</span></a> By contrast, the daughters of cases iii:a and iii:2 of this family, with two AGG interruptions and a number of CGG repeats in the range of 80–90, were affected with FXS. We consider keeping track of paediatric patients with alleles in the premutation range important, especially if they have symptoms compatible with psychomotor impairment and/or socialisation difficulties and autistic spectrum disorder.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">3</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">As a special particularity, the case of iv:4 with alleles in the condition of mosaicism is noteworthy: premutation/full-mutation, asymptomatic and with normal brain MRI. Alleles, although they showed full mutation, were not methylated, so the FMRP protein was active and could be expressed normally. The absence of methylation of the gene and the consequent production of the FMRP protein has been positively correlated with the intellectual prognosis of patients in a condition of mosaicism, which is not the case in other clinical features such as hyperactivity or autism spectrum disorder.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">20</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">In conclusion, FXS, although rare, is a disease that, given its hereditary character, is a major medical and social responsibility for health professionals. Intellectual disability, attention deficit hyperactivity disorder traits and characteristic phenotypes appear to be consistently common in patients with FXS and are relevant together with a genetic confirmation to establish an early diagnosis in these patients before 3 years of age, while also allowing us to detect possible new cases of FXS in the family or FXPOI and FXTAS that might otherwise go unnoticed. The inclusion of more consistent and sensitive techniques in the genetics laboratory will allows us to confirm a clinical diagnosis earlier and with greater reliability. It is important to combine the use of several complementary techniques to support patients’ clinical cases, as occurred in this index case.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflict of interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres690129" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Clinical observation and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Discussion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec696171" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres690128" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Observación clínica o métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Discusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec696172" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Clinical observation or methods" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Index case" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Study of the family" ] ] ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflict of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-08-15" "fechaAceptado" => "2015-11-19" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec696171" "palabras" => array:7 [ 0 => "Fragile X syndrome" 1 => "Fragile X-associated primary ovarian insufficiency" 2 => "Fragile X-associated tremor and ataxia syndrome" 3 => "Triplet repeat primer-polymerase chain reaction" 4 => "Interruptions adenine–guanine–guanine" 5 => "Intellectual disability" 6 => "1q21.1 deletion" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec696172" "palabras" => array:7 [ 0 => "Síndrome de X-frágil" 1 => "Insuficiencia ovárica primaria asociada al síndrome de X-frágil" 2 => "Síndrome de temblor-ataxia asociado al síndrome de X-frágil" 3 => "Triplet repeat primer-polymerase chain reaction" 4 => "Interrupciones Adenina-Guanina-Guanina" 5 => "Discapacidad intelectual" 6 => "Deleción 1q21.1" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The dynamic increase in the number of triplet repeats of cytosine–guanine–guanine (CGG) in the <span class="elsevierStyleItalic">FMR1</span> gene mutation is responsible for three OMIM syndromes with a distinct clinical phenotype: Fragile X syndrome (FXS) and two pathologies in adult carriers of the premutation (55–200 CGG repeats): primary ovarian insufficiency (FXPOI) and tremor–ataxia syndrome (FXTAS) associated with FXS.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Clinical observation and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">CGG mutation dynamics of the <span class="elsevierStyleItalic">FMR1</span> gene were studied in DNA samples from peripheral blood from the index case and other relatives of first, second and third degree by TP-PCR, and the percentage methylation.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Diagnosis of FXS was confirmed in three patients (21.4%), eight patients (57.1%) were confirmed in the premutation range transmitters, one male patient with full mutation/permutation mosaicism (7.1%) and two patients (14.3%) with normal study. Of the eight permutated patients, three had FXPOI and one male patient had FXTAS.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Discussion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Our study suggests the importance of making an early diagnosis of SXF in order to carry out a family study and genetic counselling, which allow the identification of new cases or premutated patients with <span class="elsevierStyleItalic">FMR1</span> gene-associated syndromes (FXTAS, FXPOI).</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Clinical observation and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Discussion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El aumento del número de repeticiones del triplete citosina-guanina-guanina (CGG), en el gen <span class="elsevierStyleItalic">FMR1</span> es responsable de 3 síndromes OMIM con fenotipo clínico bien diferenciado: síndrome de X frágil (SXF) y 2 enfermedades en adultos portadores de la premutación (55-200 repeticiones CGG): insuficiencia ovárica primaria (FXPOI) y síndrome de temblor-ataxia (FXTAS) asociado al SXF.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Observación clínica o métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se estudió la mutación dinámica CGG del gen <span class="elsevierStyleItalic">FMR1</span> en muestras de ADN de sangre periférica del caso índice y familiares de primer, segundo y tercer grado mediante TP-PCR, así como el porcentaje de metilación.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se confirmó el diagnóstico del SXF en 3 pacientes (21,4%), 8 pacientes (57,1%) se encontraban en el rango de premutación, un paciente varón con mosaicismo premutación-mutación completa (7,1%) y 2 pacientes (14,3%) con estudio normal. De los 8 pacientes premutados, 3 presentaron FXPOI y un paciente varón FXTAS.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Discusión</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Nuestro estudio muestra la importancia de realizar un diagnóstico precoz del SXF y su consecuente estudio familiar y consejo genético, que permita identificar nuevos pacientes afectos o pacientes premutados con síndromes relacionados con el gen <span class="elsevierStyleItalic">FMR1</span> (FXTAS, FXPOI).</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Observación clínica o métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Discusión" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: González-Pérez J, Izquierdo-Álvarez S, Fuertes-Rodrigo C, Monge-Galindo L, Peña-Segura JL, López-Pisón FJ. Expansión del triplete citosina-guanina-guanina: 3 casos de síndrome OMIM en una misma familia. Med Clin (Barc). 2016;146:311–315.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2300 "Ancho" => 3000 "Tamanyo" => 244724 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Family tree with the cases studied: first, second and third degree relatives from the index/test case.</p> <p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">IV:6, IV:3 and IV:2: FXS; III 1, III: 2; III: 3: FXPOI; II:1: FXTAS; IV:4: asymptomatic premutation/full mutation mosaic.</p>" ] ] 1 => 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:2 [ "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">IV:6: index case; III:7: mother of index case (second case studied); III:3: maternal aunt of index case (third case studied); II:2: maternal grandmother of the index case; II:1: maternal great uncle of the index case; IV:4: maternal cousin of the index case; III: 6: maternal uncle of the index case; III:2 and III:1: second maternal cousins of the index case; IV:1, IV:2, IV:3: third maternal cousins of the index case. Order of genetic study case IV:6 to IV:3.</p>" "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="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Case \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Phenotype \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinic \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">CGG repeats (% methylation) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AGG interruptions \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnosis (age) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IV:6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Microcephaly, elongated faces, broad forehead, large and detached ears \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intellectual impairment, attention deficit hyperactivity disorder and psychomotor impairment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allele 1<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>200<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>10 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FXS affectation (10 years-old) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">III:7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Large and detached ears \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Menopause at 44, dyslexia during childhood \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allele 1: 29<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1<br>Allele 2: 122<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3<br>Allele 3: 150<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FXS premutation (44 years-old) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">III:3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Large and detached ears \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Premature ovarian failure (POF) at age 36, epilepsy and absences in childhood. Depression and mood disorders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allele 1: 30<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1 (53%)<br>Allele 2: 94<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3 (63%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FXS premutation<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>POF: FXPOI (52 years-old) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">II:2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Large and detached ears \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allele 1: 21<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1<br>Allele 2: 84<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FXS premutation (78 years-old) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">II:1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Depression and intentional tremor (onset of symptoms at 62 years-old) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allele 1: 87<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Premutation FXS: FXTAS (77 years-old) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IV:4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Large ears \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Asymptomatic<br>Normal brain magnetic resonance imaging \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allele 1: 153<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5 (100%)<br>Allele 2: 203<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>10 (0%)<br>Allele 3: >200<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>10 (0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mosaicism<br>Premutation/full mutation (31 years-old) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">III:6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Large ears \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Asymptomatic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allele 1: 107<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Premutation FXS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">III:4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Asymptomatic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allele: 20<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">III:5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Asymptomatic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allele: 20<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">III:2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Large and detached ears \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Menopause at 40 years-old \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allele 1: 32<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1<br>Allele 2: 85<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FXS premutation<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>POF: FXPOI \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">III:1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Large and detached ears \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Menopause at 40 years-old \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allele 1: 33<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1<br>Allele 2: 87<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FXS premutation<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>POF: FXPOI \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IV:1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Detached ears \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Behavioural and mood disorders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allele 1: 30<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1 (22%)<br>Allele 2: 146<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5 (100%)<br>Allele 3: 173<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mosaicism<br>Premutation (22 years-old) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IV:2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Large and detached ears, elongated faces, prognathism and macrocephaly \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Coloboma of the iris, strabismus, intellectual impairment, attention deficit hyperactivity disorder \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allele 1: 30<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1<br>Allele 2: >200<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FXS affectation (13 years-old) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IV:3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Large and elongated ears, elongated face and macrocephalia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intellectual disabilities and attention deficit hyperactivity disorder \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allele 1: 20<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1<br>Allele 2: >200<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FXS affectation (9 years-old) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1122967.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Description of patients who have undergone genetic studies of the dynamic mutation of the <span class="elsevierStyleItalic">FMR1</span> gene (CGG triplet expansion).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0105" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Climbing the branches of a family tree: diagnosis of fragile X syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J. 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