Original article
Next generation sequencing in the diagnosis of Stargardt's disease
La secuenciación masiva (NGS) como método diagnóstico en la enfermedad de Stargardt
B. Jimenez-Rolandoa,
, S. Novalb, I. Rosa-Perezb, E. Mata Diaza, A. del Pozoc, C. Ibañezc, J.C. Sillac, V.E.F. Montañod, R. Martin-Arenasd, E. Vallespind
Corresponding author
a Servicio Oftalmología, Hospital Central de la Cruz Roja, Madrid, Spain
b Servicio Oftalmología, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
c Sección de Bioinformática, Servicio Genética INGEMM-IdiPAZ-CIBERER, Hospital Universitario La Paz, Madrid, Spain
d Sección de Genómica Estructural y Funcional, Servicio Genética INGEMM-IdiPAZ-CIBERER, Hospital Universitario La Paz, Madrid, Spain
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"apellidos" => "Vallespin" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Servicio Oftalmología, Hospital Central de la Cruz Roja, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio Oftalmología, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Sección de Bioinformática, Servicio Genética INGEMM-IdiPAZ-CIBERER, Hospital Universitario La Paz, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Sección de Genómica Estructural y Funcional, Servicio Genética INGEMM-IdiPAZ-CIBERER, Hospital Universitario La Paz, Madrid, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La secuenciación masiva (NGS) como método diagnóstico en la enfermedad de Stargardt" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1218 "Ancho" => 1650 "Tamanyo" => 155349 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">(A and B) Case 1. (C and D) Case 2. Autofluorescense of both cases suggesting bull's-eye maculopathy and absence of flecks.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Stardgardt's disease is the most frequent macular dystrophy in the pediatric and adult age, appearing in 1/10,000 inhabitants. Typically, it expresses in the first 2 decades of life with central, bilateral and progressive visual acuity (VA) reduction. There is a subtype which appears later and is a diagnostic challenge against age-related macular degeneration. Clinically, findings comprise macular retinal atrophy images together with lesions known as <span class="elsevierStyleItalic">flecks</span> that indicate retina pigment epithelium and overlying photoreceptor layer alterations.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Stardgardt's macular dystrophy is genetically heterogenic and could present a recessive autosomic inheritance pattern produced by mutations in gene <span class="elsevierStyleItalic">ABCA4</span> (STGD1, OMIM <a href="omim:248200">248200</a>), or more rarely dominant inheritance due to involvement of genes <span class="elsevierStyleItalic">ELOVL4</span> (STGD3 OMIM <a href="omim:600110">600110</a>) and <span class="elsevierStyleItalic">PROM1</span> (STGD4 OMIM <a href="omim:603786">603786</a>). In addition, the frequency of heterozygote mutation carriers in <span class="elsevierStyleItalic">ABCA4</span> is high, reaching 5% of the population, which means that pseudo-autosomal dominant inheritance could occur.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">1</span></a> The clinic phenotype is the result of the combination of the severity of mutated alleles, giving rise to the range known as ABCA4 retinopathies that comprises age-related macular degeneration in heterozygote subjects, through Stardgardt's disease, cone and rod dystrophy and finally <span class="elsevierStyleItalic">retinitis pigmentosa</span> in its severest forms (<a href="http://www.omim.org/">omim.org</a>).</p><p id="par0015" class="elsevierStylePara elsevierViewall">Suspect diagnostic is clinic although a genetic study is necessary for confirmation due to prognostic variability depending on underlying mutations as it is possible to detect asymptomatic carriers or patients in early stages of the disease due to the development of gene therapies. Even though at this time and there is no effective treatment, numerous clinic trials in phase I/II are in course which, together with the progress of gene edition by means of CRISPR, give rise to promising expectations for the near future.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">2–5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In recent years, the development of massive sequencing (NGS) has become a valuable tool for the genetic study of these patients because it enables sequencing in very short time and low cost, ranging from a single gene up to the complete genome in a single essay, and is highly applicable for diagnosing macular dystrophies.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">6</span></a> Two cases of Stargardt's disease are presented, one in the initial stage with incomplete phenotype, genetically confirmed through NGS.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Clinic case reports</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Case 1</span><p id="par0025" class="elsevierStylePara elsevierViewall">Male patient, 29, who consulted due to progressive VA deterioration starting 3 years earlier. No relevant personal or familial antecedents were referred. Baseline VA was of 1 in both eyes, measured in the decimal scale. Ocular fundus (OF) exhibited nonspecific alteration of the retina pigment epithelium (RPE) with brunescent reflex (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A and B). In the course of 2 years, VA had diminished 3 lines while in the last checkup, 7 years after the first one, BA was 0.3 in the right eye and 0.15 in the left eye. OF image progressed to central atrophy without drusen or typical flecks. Optic coherence tomography (OCT) showed severe central macular atrophy with image of small foveolar optic gap (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A and B). Autofluorescense (AF) and fluorescein angiography (FAG) showed bull's-eye maculopathy with hyper-and hypoautofluoerescent dots and absence of flecks and choroidal silence (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A and B). Diffuse electroretinogram (ERG) produced normal results.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">A genetic study was performed by means of NGS (see below). Two pathogenic mutations were found in heterozygosis for gene <span class="elsevierStyleItalic">ABCA4</span>: c.G5882A:p.Gly1961Glu in exon 42 (frequency in European population of ExAc 0.0047. SIFT 0. PolyPhen 0.99) and c.C3056T:p.T1019M in exon 21 (frequency in the European population ExAc 0.000041. SIFT 0. PolyPhen 1) (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Case 2</span><p id="par0035" class="elsevierStylePara elsevierViewall">Female, 22, who consulted due to progressive VA deterioration with one year evolution. No relevant personal or familial antecedents were referred. Exploration revealed nonspecific macular lesion with beaten bronze appearance (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C and D). After one year, VA had diminished to 0.1 in the right eye and 0.15 in the left eye. OCT revealed severe macular atrophy and FAG hypoautofluorescent image, suggesting bull's-eye maculopathy (<a class="elsevierStyleCrossRefs" href="#fig0010">Figs. 2C, D and 3C, D</a>). No typical Stargardt disease flecks could be observed, while FAG showed a characteristic choroidal silence image suggesting said disease (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>). Diffuse ERG was normal.</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">A genetic study was performed by means of NGS (see below). Two pathogenic mutations were found in heterozygosis for gene <span class="elsevierStyleItalic">ABCA4</span>: c.5882G>A:p.Gly1961Glu in exon 42 (frequency in the European population ExAc 0.0047. SIFT 0. PolyPhen 0.99) and c.287del:p.Asn96Thrfs*19 in exon 3 (mutation not described in the ExAC and EVS ni dbSNP databases) (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Genetic diagnostic methodology</span><p id="par0045" class="elsevierStylePara elsevierViewall">Both patients were studied with the NGS Oft_v1.0 panel with customized design in the INGEMM and utilized in clinic routine for diagnosing ocular disease patients with suspected genetic origin, including maculopathy. Said panel comprises 298 genes and the exon region as well as adjacent areas are studied (10<span class="elsevierStyleHsp" style=""></span>bp).</p><p id="par0050" class="elsevierStylePara elsevierViewall">The Oft_v1.0 panel was built utilizing NimbleDesign software (Preferred Close Matches: 3 and Maximum Close Matches: 20). NGS protocol was SeqCapEZ (SeqCapEZ SR, Roche, Potsdam,RFA California, USA) SR by NimbleDesign, and the panel run was carried out in a NextSeq500 (Illumina).</p><p id="par0055" class="elsevierStylePara elsevierViewall">For analyzing results, the biocomputation team designed a biocomputation analysis system focused on identifying specific polymorphisms, insertion and deletion of small DNA fragments as well as of larger size structural variants in the capture regions included in the massive sequencing panels. The system comprises sample preprocessing, alignment of readings against a reference genome, functional identification and annotation of variance and filtering thereof. The software and databases utilized in the biocomputing analysis were: Bowtie2 v2.0.0, Picard-tools 1.27, Samtools v0.1.19-44428cd, GenomeAnalysisTK v2.6-5. SnpEff 3.5e. Databases: dbNSFP version 2.7; dbSNP v137; ClinVar date 20140703. Reference human genome: hg19. Bio computing tools for predicting pathogenicity: CADD, SIFT, Polyphen, MutationTaster, Fathmm, LR and splicing applications.</p><p id="par0060" class="elsevierStylePara elsevierViewall">All detected alterations considered to be pathogenic or possibly pathogenic were confirmed through classic or Sanger sequencing and reported to patients.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0065" class="elsevierStylePara elsevierViewall">Patients were diagnosed as composite heterozygote for gene <span class="elsevierStyleItalic">ABCA4</span>, which is responsible for the Stargardt STGD1 disease. Both patients exhibit mutation Gly1961Glu, which explains phenotype similarity. Stargardt's disease debuts with progressive bilateral VA reduction and central or paracentral scotomae in the 2 first decades of life. There is a second peak after 30, and a third group of patients in whom the disease appears in the sixth decade of life. Age of onset is inversely related to prognostic severity.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">7</span></a> Estimated VA impairment is approximately 0.3 Snellen scale lines per year. However, patients exhibiting better baseline VA experience greater impairment, losing up to one line per year in patients with good baseline VA.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">7</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">OF and imaging techniques such as OCT, FA, FAG and ERG are at present the basis for diagnosing macular dystrophies. In OF we find different phenotypes, such as macular central atrophy accompanied by flecks, <span class="elsevierStyleItalic">fundus flavimaculatus</span> and bull's-eye maculopathy. Initially, it debuts as a slight retina pigment epithelium (RPE) alteration or beaten bronze appearance that progressively evolves to macular atrophy. Flecks are yellowish lesions having various shapes and forms that respond to accumulation of lipofucsin at the RPE level and are distributed in the posterior pole around the temporal vascular arcs and exhibit autofluorescent properties. OCT depicts said lesions as small hyper-reflective aggregates at the RPE level that grow crossing the ellipsoid line (IS/OS) and the external limiting membrane (ELM), generating a thinned internal nuclear layer.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">8</span></a> In addition, ELM becomes thicker, the IS/OS is disrupted, a subfoveolar gap emerges with hyper-reflective detritus inside and external nuclear layer thinning, as well as severe central atrophy in the final stages.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">9</span></a> Diminished macular thickness is directly correlated to VA loss.</p><p id="par0075" class="elsevierStylePara elsevierViewall">FA detects the presence of flecks and bull's-eye maculopathy at an early stage. It allows the differentiation of 3 types: (a) presence of hyper-autofluorescent ring around a hypo-autofluorescent central area; (b) type A with absence of ring; and (c) dotted macular aspect.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">8</span></a> Quantitive FA for indirect individual measurement of the amount of lipofucsin <span class="elsevierStyleItalic">in vivo</span> is being researched.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">10</span></a> In contrast with FA, FAG will display bull's-eye maculopathy and flecks as hyperfluorescence. The characteristic image will be choroidal silence due to blockage of the generalized lipofucsin aggregates in the RPE.</p><p id="par0080" class="elsevierStylePara elsevierViewall">According to Lois et al.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">11</span></a>, 3 diffuse ERG groups can be classified: type I, with normal diffuse ERG; type II, with normal scotopic diffuse but altered photopic ERG; and type III, with altered photopic and scotopic diffuse ERG. Electro-oculogram (EOG) is altered according to the degree of lesions.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">9,12,13</span></a> ERG and EOG alterations occur more frequently in the presence of flecks.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">13</span></a> Case 1 exhibited bull's-eye maculopathy type B, with slight foveal gap appearance in OCT and absence of choroidal silence, whereas case 2 exhibited onset of bull's-eye maculopathy that can be classified as type B and choroidal silence image in FAG. According to the phenotypic classification of Lois, both cases would be phenotype 1, with good prognosis in what concerns peripheral retina involvement.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">11</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">After the phenotype has been assessed, diagnostic confirmation must be requested through genetic study. Gene <span class="elsevierStyleItalic">ABCA4</span> codes for a protein belonging to a family of ABCR ATPases that is located in the discs of the external portion of photoreceptors and has the function of evacuating retinol metabolism degradation product to RPE cells. The alteration thereof gives rise to an aggregate of N-retinildene-N-retinilethanolamine in the last instance, a component of lipofucsin which, due to its toxicity, produces in the first place the death of RPE cells and subsequently of the photoreceptors.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">14</span></a> NGS cost reductions have improved accessibility of genetic study and is particularly applicable in this case. On the one hand, it allows for the sequencing of all relevant genes for a same process and discard other diseases with similar phenotypes. On the other hand, gene <span class="elsevierStyleItalic">ABCA4</span> exhibits peculiar qualities: it is situated in the 1p22 region and contains 50 exons. The sequencing of said gene through the Sanger technique would involve more time and costs. In addition, it is a highly polymorphic gene that has been described in over 500 mutations. Accordingly, the use of genotyping micro-arrays could omit a high percentage of undescribed mutations.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">15</span></a> For instance, as the mutation Asn96Thrfs*19 exhibited by case 2 was not described in the database, it might not be found in a micro-array. Despite NGS being a powerful tool, it is important to know its limitations. In the majority of cases, the only sequencing performed is that of the coding regions, which means that mutations in intronic regions would not detected. In this regard, heterozygote patients for this gene are a diagnostic challenge because the population frequency of heterozygotes is high and for this reason, in the presence of very evident phenotypes, the existence of an unknown intronic mutation that explains the condition is presumed. Additional limitations of the technique are high complexity regions and large reorderings which must be known beforehand and reported to the patient.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">6,15</span></a> Accordingly, good phenotypic characterization prior to a genetic study is extremely important.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Mutation Gly1961Glu, exhibited by the present patients, is one of the most frequent mutations for gene <span class="elsevierStyleItalic">ABCA4</span>, because it is found in up to 10% of patients with Stargardt's disease of European descent.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">12</span></a> Various studies have established a genotype-phenotype correlation for mutation Gly1961Glu that has been related to slight-moderate involvement limited to the macular area and bull's-eye maculopathy phenotype, the B-type being most frequent for this mutation, with early disorganization of photoreceptors at the central level, absence of flecks and choroidal silence in FAG. Gly1961Glu is associated to normal diffuse ERG with alteration of multifocal ERG and, in OCT, to the presence of a foveal optic gap.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">9,12,16</span></a> Gly1961Glu is a missense mutation that diminishes the ATPase activity. It is regarded as pathogenic and the genotype-phenotype relationship is influenced by other factors such as the severity of the second allele, the presence of additional mutations in <span class="elsevierStyleItalic">ABCA4</span> or unknown genetic as well as environmental modifying factors.<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">12,16</span></a> Mutation c.287del:p.Asn96Thrfs*19 was previously described by Spanish authors and does not appear in the ExAC and EVS databases, which suggests a foundation effect of this mutation in the Spanish population.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">17</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Even though there is no healing treatment for Stargardt's disease, <span class="elsevierStyleItalic">knockout ABCA4</span> (−/−) mice have demonstrated increases in the lipofucsin aggregation with vitamin A supplements and when exposed to ultraviolet light. Accordingly, in contrast with <span class="elsevierStyleItalic">retinitis pigmentosa</span>, it is important to request these patients to refrain from taking vitamin A supplements as well as avoiding exposure to sunlight.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">12</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">There are several research lines for treating Stargardt's disease in phase I/II (<a href="http://www.clinicaltrials.gov/">clinicaltrials.gov</a>) focused on pharmacology, gene therapy and stem cell regeneration. Some examples are the TEASE trial in phase II (clinicaltrials.gov <a href="ctgov:NCT02402660">NCT02402660</a>) that assesses the effects of ALK-001 (C20-D3-Retinyl Acetate), a chemically modified vitamin A that does not produce vitamin A dimers that accumulate and generate toxicity in the presence of a defective <span class="elsevierStyleItalic">ABCA4</span> protein, or the clinic trial registered at clinicaltrials.gov under number <a href="ctgov:NCT01345006">NCT01345006</a> in phase I/II that consists in subretinal administration of embryo stem cells to cover said atrophy areas. Adequate tolerance has been demonstrated, without the appearance of evident side effects in a four-year follow-up period, although adverse effects have appeared in relation to surgery or added immunosuppressants treatment. To overcome this problem, other trials have focused on the use of induced stem cells from the same patient.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">5</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Finally, gene therapy has shown an interest in genetic diseases such as Stargardt's disease. Gene therapy consisting in the addition of the gene has been leading this area until relatively recently. Research has focused on the use of dual AVA vectors, or lentivirus (SAR 422459: clinicaltrials.gov <a href="ctgov:NCT01367444">NCT01367444</a>), as gene <span class="elsevierStyleItalic">ABCA4</span> presents a larger size (>6<span class="elsevierStyleHsp" style=""></span>kb) for AVA vectors most utilized in the retina (<5<span class="elsevierStyleHsp" style=""></span>kb).<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">2,3</span></a> New gene edition therapies with CRISPR/Cas9 technologies could specifically repair a genetic alteration without requiring the introduction of entire genes and, in addition, as a permanent repair.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">4</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In conclusion, NGS is particularly useful in Stargardt's disease because gene <span class="elsevierStyleItalic">ABCA4</span> has a large size and high polymorphic heterogeneity, which translates into broad clinic variability. Due to the large size of this gene, sequencing costs with Sanger technique far exceed that of NGS, which also enables expanding the study to other more infrequent genes that cause Stargardt's disease. Genetic diagnostic confirmation is important to establish a genotype-phenotype relationship as in the 2 cases presented herein, to perform adequate genetic counseling as well as family study at the patient's request in order to anticipate the appearance of the disease. In addition, the progress of clinic trials developing gene therapies, which could be available in the midterm, makes it essential to genetically verify the disease.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflict of interests</span><p id="par0115" class="elsevierStylePara elsevierViewall">No conflict of interests was declared by the authors</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres993659" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec957095" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres993658" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec957096" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Clinic case reports" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Case 1" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Case 2" ] ] ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Genetic diagnostic methodology" ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflict of interests" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-01-29" "fechaAceptado" => "2017-03-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec957095" "palabras" => array:3 [ 0 => "Stardgardt's disease" 1 => "ABCA4" 2 => "Next generation sequencing (NGS)" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec957096" "palabras" => array:3 [ 0 => "Enfermedad de Stargardt" 1 => "ABCA4" 2 => "Next generation sequencing" ] ] ] ] "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">Stargardt's disease is the most frequent form of inherited macular dystrophy in children and adults. It is a genetic eye disorder caused by mutations in <span class="elsevierStyleItalic">ABCA4</span> gene with an autosomal recessive inheritance. <span class="elsevierStyleItalic">ABCA4</span> is a very polymorphic and large gene containing 50 exons. The development of next generation sequencing (NGS) can be used for the genetic diagnosis of this disease.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A report is presented on two patients with a clinical diagnosis of Stargardt's disease whose genetic confirmation was performed by a NGS panel of 298 genes.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Clinically, the patients showed bull's eye maculopathy and absence of flecks, and genetically they shared the Gly1961Glu mutation that could explain their common phenotype, together with c.C3056T:p.T1019M for case 1, and c.287del:p.Asn96Thrfs*19 for case 2.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">NGS is particularly useful in the diagnosis of Stargardt's disease as <span class="elsevierStyleItalic">ABCA4</span> is a large gene with a high allelic heterogeneity that causes a wide range of clinical manifestations.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "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">La enfermedad de Stargardt es la maculopatía más frecuente en la edad infantil y adulta. Presenta un origen genético por afectación principalmente del gen <span class="elsevierStyleItalic">ABCA4</span> con herencia autosómica recesiva. Se trata de un gen con características especiales por su gran tamaño y comportamiento, mostrando una elevada tasa de mutaciones. La aparición, desarrollo y accesibilidad económica de las técnicas de secuenciación masiva permiten realizar el diagnóstico genético de la enfermedad de Stargardt.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se presentan 2 casos clínicos diagnosticados genéticamente de enfermedad de Stargardt mediante la realización de un panel de secuenciación masiva de 298 genes.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Los pacientes presentaban un fenotipo de maculopatía de ojo de buey con ausencia de <span class="elsevierStyleItalic">flecks</span> y las siguientes mutaciones: c.G5882A:p.Gly1961Glu y c.C3056T:p.T1019M para el caso 1; c.G5882A:p.Gly1961Glu y c.287del:p.Asn96Thrfs*19 para el caso 2. Ambos pacientes comparten la mutación c.G5882A:p.Gly1961Glu que explica su fenotipo similar característico.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La secuenciación masiva es especialmente útil en la enfermedad de Stargardt, pues el gen <span class="elsevierStyleItalic">ABCA4</span> presenta un gran tamaño y elevada heterogeneidad polimórfica, que se traduce en una amplia variabilidad clínica.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Jimenez-Rolando B, Noval S, Rosa-Perez I, Mata Diaz E, del Pozo A, Ibañez C, et al. La secuenciación masiva (NGS) como método diagnóstico en la enfermedad de Stargardt. Arch Soc Esp Oftalmol. 2018;93:119–125.</p>" ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1488 "Ancho" => 1650 "Tamanyo" => 220870 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">(A and B) Case 1. (C and D) Case 2. Color retinograph showing RPE beaten bronze-like alteration.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1115 "Ancho" => 1650 "Tamanyo" => 407778 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">(A and B) Case 1. (C and D) Case 2. Optical coherence tomography showing central atrophy in both patients and foveolar optic gap in case 1 (arrow).</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1218 "Ancho" => 1650 "Tamanyo" => 155349 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">(A and B) Case 1. (C and D) Case 2. Autofluorescense of both cases suggesting bull's-eye maculopathy and absence of flecks.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1232 "Ancho" => 1750 "Tamanyo" => 354953 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">NGS study. Visualization of mutations with Integrated Genome Viewer population frequencies</p>" ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 886 "Ancho" => 1010 "Tamanyo" => 117266 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Fluorescein angiograph of case 2 showing the typical choroidal silence image.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:17 [ 0 => array:3 [ "identificador" => "bib0090" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Phenotypic variation in a family with pseudodominant stargardt disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R.M. 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