Whole exome sequencing in dominant cataract identifies a new causative factor, CRYBA2, and a variety of novel alleles in known genes. Hum Genet 2013 Jul;132(7):761-70
Date
03/20/2013Pubmed ID
23508780Pubmed Central ID
PMC3683360DOI
10.1007/s00439-013-1289-0Scopus ID
2-s2.0-84879499591 (requires institutional sign-in at Scopus site) 75 CitationsAbstract
Pediatric cataracts are observed in 1-15 per 10,000 births with 10-25 % of cases attributed to genetic causes; autosomal dominant inheritance is the most commonly observed pattern. Since the specific cataract phenotype is not sufficient to predict which gene is mutated, whole exome sequencing (WES) was utilized to concurrently screen all known cataract genes and to examine novel candidate factors for a disease-causing mutation in probands from 23 pedigrees affected with familial dominant cataract. Review of WES data for 36 known cataract genes identified causative mutations in nine pedigrees (39 %) in CRYAA, CRYBB1, CRYBB3, CRYGC (2), CRYGD, GJA8 (2), and MIP and an additional likely causative mutation in EYA1; the CRYBB3 mutation represents the first dominant allele in this gene and demonstrates incomplete penetrance. Examination of crystallin genes not yet linked to human disease identified a novel cataract gene, CRYBA2, a member of the βγ-crystallin superfamily. The p.(Val50Met) mutation in CRYBA2 cosegregated with disease phenotype in a four-generation pedigree with autosomal dominant congenital cataracts with incomplete penetrance. Expression studies detected cryba2 transcripts during early lens development in zebrafish, supporting its role in congenital disease. Our data highlight the extreme genetic heterogeneity of dominant cataract as the eleven causative/likely causative mutations affected nine different genes, and the majority of mutant alleles were novel. Furthermore, these data suggest that less than half of dominant cataract can be explained by mutations in currently known genes.
Author List
Reis LM, Tyler RC, Muheisen S, Raggio V, Salviati L, Han DP, Costakos D, Yonath H, Hall S, Power P, Semina EVAuthors
Deborah M. Costakos MD Chair, Professor in the Ophthalmology and Visual Sciences department at Medical College of WisconsinElena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultAlleles
Amino Acid Substitution
Animals
Cataract
Child, Preschool
DNA Mutational Analysis
Exome
Female
Gene Expression Regulation, Developmental
Genes, Dominant
Genetic Diseases, Inborn
Humans
Infant
Male
Mutation, Missense
Zebrafish
Zebrafish Proteins
beta-Crystallin A Chain
