RESUMO
BACKGROUND: NGS-based genetic diagnosis has completely revolutionized the human genetics field. In this study, we have aimed to identify new genes and mutations by Whole Exome Sequencing (WES) responsible for inherited retinal dystrophies (IRD). METHODS: A cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES. Initial prioritization analysis included around 300 IRD-associated genes. In non-diagnosed families a search for pathogenic mutations in novel genes was undertaken. RESULTS: Genetic diagnosis was attained in 18 families. Moreover, a plausible candidate is proposed for 10 more cases. Two thirds of the mutations were novel, including 4 chromosomal rearrangements, which expand the IRD allelic heterogeneity and highlight the contribution of private mutations. Our results prompted clinical re-evaluation of some patients resulting in assignment to a syndromic instead of non-syndromic IRD. Notably, WES unveiled four new candidates for non-syndromic IRD: SEMA6B, CEP78, CEP250, SCLT1, the two latter previously associated to syndromic disorders. We provide functional data supporting that missense mutations in CEP250 alter cilia formation. CONCLUSION: The diagnostic efficiency of WES, and strictly following the ACMG/AMP criteria is 55% in reported causative genes or functionally supported new candidates, plus 30% families in which likely pathogenic or VGUS/VUS variants were identified in plausible candidates. Our results highlight the clinical utility of WES for molecular diagnosis of IRD, provide a wider spectrum of mutations and concomitant genetic variants, and challenge our view on syndromic vs non-syndromic, and causative vs modifier genes.
Assuntos
Exoma , Mutação Puntual , Distrofias Retinianas/genética , Animais , Autoantígenos/genética , Autoantígenos/fisiologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/fisiologia , Aberrações Cromossômicas , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linhagem , Semaforinas/genética , Semaforinas/fisiologia , Análise de Sequência de DNA , Canais de Sódio/genética , Canais de Sódio/fisiologiaRESUMO
PURPOSE: To describe the first case that the authors are aware of frosted branch angiitis associated with Epstein-Barr virus infection. METHODS: Case report. RESULTS: A 7-year-old boy presented with bilateral decreased visual acuity. Funduscopy showed a typical image of frosted branch angiitis. He was started on treatment with intravenous steroids and acyclovir. Serological testing was positive for anti-Epstein-Barr virus IgM antibodies. Anti-Epstein-Barr virus IgG antibodies tested positive later. During follow-up, the venous sheathing decreased. Three months later funduscopy showed no abnormalities. CONCLUSION: Epstein-Barr virus infection should be considered in patients presenting with the typical clinical manifestations of this syndrome.
