title: Sporadic and Familial Congenital Cataracts: Mutational Spectrum and New Diagnoses Using Next-Generation Sequencing.
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.
authors.affiliation: 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.|Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.|Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.|Discipline of Paediatrics and Child Health, and Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, New South Wales, Australia.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Ma
authors.affiliation: 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.|Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.|Discipline of Ophthalmology, Sydney Medical School, University of Sydney, New South Wales, Australia.
authors.forename: John R
authors.initials: JR
authors.lastname: Grigg
authors.affiliation: Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.|Department of Molecular Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
authors.forename: Gladys
authors.initials: G
authors.lastname: Ho
authors.affiliation: 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.
authors.forename: Ivan
authors.initials: I
authors.lastname: Prokudin
authors.affiliation: Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.|Department of Molecular Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Farnsworth
authors.affiliation: Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.|Department of Molecular Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Holman
authors.affiliation: 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.
authors.forename: Anson
authors.initials: A
authors.lastname: Cheng
authors.affiliation: 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.|Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.|Discipline of Ophthalmology, Sydney Medical School, University of Sydney, New South Wales, Australia.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Billson
authors.affiliation: Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.|Discipline of Ophthalmology, Sydney Medical School, University of Sydney, New South Wales, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Martin
authors.affiliation: Discipline of Ophthalmology, Sydney Medical School, University of Sydney, New South Wales, Australia.
authors.forename: Clare
authors.initials: C
authors.lastname: Fraser
authors.affiliation: Department of Medical Genetics, Sydney Children's Hospital, Sydney, New South Wales, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Mowat
authors.affiliation: Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Smith
authors.affiliation: Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.|Discipline of Paediatrics and Child Health, and Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, New South Wales, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.affiliation: 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.|Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.|Discipline of Ophthalmology, Sydney Medical School, University of Sydney, New South Wales, Australia.
authors.forename: Maree
authors.initials: M
authors.lastname: Flaherty
authors.affiliation: Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.|Discipline of Paediatrics and Child Health, and Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, New South Wales, Australia.|Department of Molecular Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
authors.forename: Bruce
authors.initials: B
authors.lastname: Bennetts
authors.affiliation: 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.|Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.|Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.|Discipline of Paediatrics and Child Health, and Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, New South Wales, Australia.
authors.forename: Robyn V
authors.initials: RV
authors.lastname: Jamieson
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D002386:Cataract / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology / Q000379:methods; D017630:Connexins / Q000235:genetics; D003459:Crystallins / Q000235:genetics; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D050172:Genes, X-Linked; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D008565:Membrane Proteins; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D000071841:PAX6 Transcription Factor / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D000099264:Connexin 50
chemical_list: D017630:Connexins; D003459:Crystallins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D000071841:PAX6 Transcription Factor; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D012097:Repressor Proteins; D000099264:Connexin 50; C411984:BCOR protein, human; C495607:MAF protein, human; C488621:NHS protein, human; C082917:GJA3 protein, human
keywords: congenital cataract; eye; microcornea; microphthalmia; next-generation sequencing