Sporadic and Familial Congenital Cataracts: Mutational Spectrum and New Diagnoses Using Next‐Generation Sequencing |
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| Authors: | Alan S. Ma John R. Grigg Gladys Ho Ivan Prokudin Elizabeth Farnsworth Katherine Holman Anson Cheng Frank A. Billson Frank Martin Clare Fraser David Mowat James Smith John Christodoulou Maree Flaherty Bruce Bennetts Robyn V. Jamieson |
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| Affiliation: | 1. Eye Genetics Research, The Children's Hospital at Westmead, Save Sight Institute, Children's Medical Research Institute, University of Sydney, Sydney, New South Wales, Australia;2. Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia;3. Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, New South Wales, Australia;4. Discipline of Paediatrics and Child Health, and Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, New South Wales, Australia;5. Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia;6. Discipline of Ophthalmology, Sydney Medical School, University of Sydney, New South Wales, Australia;7. Department of Molecular Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia;8. Department of Medical Genetics, Sydney Children's Hospital, Sydney, New South Wales, Australia |
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| Abstract: | Congenital cataracts are a significant cause of lifelong visual loss. They may be isolated or associated with microcornea, microphthalmia, anterior segment dysgenesis (ASD) and glaucoma, and there can be syndromic associations. Genetic diagnosis is challenging due to marked genetic heterogeneity. In this study, next‐generation sequencing (NGS) of 32 cataract‐associated genes was undertaken in 46 apparently nonsyndromic congenital cataract probands, around half sporadic and half familial cases. We identified pathogenic variants in 70% of cases, and over 68% of these were novel. In almost two‐thirds (20/33) of these cases, this resulted in new information about the diagnosis and/or inheritance pattern. This included identification of: new syndromic diagnoses due to NHS or BCOR mutations; complex ocular phenotypes due to PAX6 mutations; de novo autosomal‐dominant or X‐linked mutations in sporadic cases; and mutations in two separate cataract genes in one family. Variants were found in the crystallin and gap junction genes, including the first report of severe microphthalmia and sclerocornea associated with a novel GJA8 mutation. Mutations were also found in rarely reported genes including MAF, VIM, MIP, and BFSP1. Targeted NGS in presumed nonsyndromic congenital cataract patients provided significant diagnostic information in both familial and sporadic cases. |
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| Keywords: | next‐generation sequencing congenital cataract microcornea microphthalmia eye |
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