RESUMO
Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.
Assuntos
Proteínas de Transporte/genética , Distrofias de Cones e Bastonetes/genética , Oftalmopatias Hereditárias/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação/genética , Distrofias Retinianas/genética , Adulto , Idoso , Criança , Pontos de Quebra do Cromossomo , Simulação por Computador , Distrofias de Cones e Bastonetes/fisiopatologia , Variações do Número de Cópias de DNA/genética , Eletrorretinografia , Oftalmopatias Hereditárias/fisiopatologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Distrofias Retinianas/fisiopatologiaRESUMO
PURPOSE: We intend to describe an uncommon presentation of X-linked juvenile retinoschisis (XLRS) in a 17-year-old boy showing a macular demarcation line in the right eye and an inferior peripheral bullous retinoschisis in both right and left eye, at his first ophthalmologic examination. METHODS: The patient underwent a complete ophthalmologic examination including best-corrected visual acuity assessment, anterior segment and dilated fundus examination, ultra-wide-field retinography, spectral-domain optical coherence tomography, fundus autofluorescence, fluorescein angiography, electroretinography, visual field test, and genetic molecular testing. RESULTS: We report a rare case of genetically confirmed XLRS, presenting as a unilateral mildly-pigmented macular demarcation line (advanced sequel of unilateral spontaneous retinal reattachment of a previous retinal detachment or bullous retinoschisis) without foveoschisis in the fellow eye. CONCLUSION: XLRS is the most frequent cause of macular retinoschisis. The hallmark of XLRS is the evidence of a foveoschisis presenting with a characteristic spoke-wheel aspect in patients younger than 30 years of age. It is important to recognize uncommon presentations of XLRS so that the correct diagnosis is made, in order to provide the patients with appropriate genetic counseling and therapeutic care.
Assuntos
Retinosquise , Adolescente , Eletrorretinografia , Angiofluoresceinografia , Humanos , Masculino , Retina , Retinosquise/diagnóstico , Retinosquise/genética , Tomografia de Coerência Óptica , Acuidade VisualRESUMO
Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. RIMS2 regulates synaptic membrane exocytosis. Data mining of human adult bulk and single-cell retinal transcriptional datasets revealed predominant expression in rod photoreceptors, and immunostaining demonstrated RIMS2 localization in the human retinal outer plexiform layer, Purkinje cells, and pancreatic islets. Additionally, nonsense variants were shown to result in truncated RIMS2 and decreased insulin secretion in mammalian cells. The identification of a syndromic stationary congenital IRD has a major impact on the differential diagnosis of syndromic congenital IRD, which has previously been exclusively linked with degenerative IRD.
