RESUMO
Nowadays, exome sequencing is a robust and cost-efficient genetic diagnostic tool already implemented in many clinical laboratories. Despite it has undoubtedly improved our diagnostic capacity and has allowed the discovery of many new Mendelian-disease genes, it only provides a molecular diagnosis in up to 25-30% of cases. Here, we comprehensively evaluate the results of a large sample set of 4974 clinical exomes performed in our laboratory over a period of 5 years, showing a global diagnostic rate of 24.62% (1391/4974). For the evaluation we establish different groups of diseases and demonstrate how the diagnostic rate is not only dependent on the analyzed group of diseases (43.12% in ophthalmological cases vs 16.61% in neurological cases) but on the specific disorder (47.49% in retinal dystrophies vs 24.02% in optic atrophy; 18.88% in neuropathies/paraparesias vs 11.43% in dementias). We also detail the most frequent mutated genes within each group of disorders and discuss, on our experience, further investigations and directions needed for the benefit of patients.
Assuntos
Atrofia Óptica , Distrofias Retinianas , Humanos , Exoma/genética , Sequenciamento do Exoma , Distrofias Retinianas/genética , Atrofia Óptica/genéticaRESUMO
Despite the improved accuracy of next-generation sequencing (NGS), it is widely accepted that variants need to be validated using Sanger sequencing before reporting. Validation of all NGS variants considerably increases the turnaround time and costs of clinical diagnosis. We comprehensively assessed this need in 1109 variants from 825 clinical exomes, the largest sample set to date assessed using Illumina chemistry reported. With a concordance of 100%, we conclude that Sanger sequencing can be very useful as an internal quality control, but not so much as a verification method for high-quality single-nucleotide and small insertion/deletions variants. Laboratories might validate and establish their own thresholds before discontinuing Sanger confirmation studies. We also expand and validate 23 copy number variations detected by exome sequencing in 20 samples, observing a concordance of 95.65% (22/23).
Assuntos
Exoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Mutação/genética , Variações do Número de Cópias de DNA/genética , Humanos , Reprodutibilidade dos TestesAssuntos
Cromossomos Humanos X , Proteínas do Olho/genética , Ligação Genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Mutação , Retinose Pigmentar/genética , Saúde da Família , Proteínas de Ligação ao GTP , Humanos , Masculino , Linhagem , Fenótipo , EspanhaRESUMO
INTRODUCTION: Dominant autosomic ataxias include a group of neurodegenerative diseases characterized by the abnormal expansion of triplets. CASE REPORT: Male aged 33, with expansion of the SCA 8 gene (100 repetitions), who presented a clinical picture compatible with a pancerebellar syndrome. The patient had been diagnosed 11 years earlier as suffering from previously of histiocytosis X. A clinico genetic study was conducted on the patient and several members of his family (parents and two sisters). Both sisters and the father were found to be carriers of the expansion (110 and 150 repetitions, respectively), and are currently asymptomatic. RESULTS AND DISCUSSION: There is no relation between the number of repetitions and the age of onset of the disease. The normal interval in our population oscillates between 16 37 repetitions, and the pathological interval has not been well determined. There may be a relation between the SCA 8 form and histiocytosis X.
Assuntos
Ataxias Espinocerebelares/genética , Adulto , Feminino , Humanos , Masculino , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , RNA Longo não Codificante , RNA não Traduzido , EspanhaRESUMO
Introducción. Las ataxias autosómicas dominantes son un grupo de enfermedades neurodegenerativas causadas por la expansión anormal de tripletes. Caso clínico. Varón de 33 años, con expansión en el gen SCA8 (100 repeticiones), que presentó un cuadro clínico compatible con un síndrome pancerebeloso. El paciente se había diagnosticado 11 años antes de histiocitosis X. Se ha realizado un estudio clinicogenético del paciente y varios miembros de la familia (padres y dos hermanas); han resultando portadores de la expansión las dos hermanas y el padre del probando (110 y 150 repeticiones, respectivamente), y se encuentran asintomáticos. Resultados y discusión. No existe relación entre el número de repeticiones y la edad de aparición de la enfermedad. El intervalo normal en nuestra población oscila entre 16-37 repeticiones, y el intervalo patológico no se ha determinado bien. Es posible que exista una relación entre la forma SCA8 y la histiocitosis X (AU)
