Whole exome sequencing in dominant cataract identifies a new causative factor, CRYBA2, and a variety of novel alleles in known genes

Abstract

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.

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

“…2013). Data were evaluated for mutations in 203 genes known to be involved in ocular development (Schilter et al.…”

Zebrafish—on the move towards ophthalmological research

“…64 Some studies have described zebrafish as a promising animal model to study dominant congenital cataracts. 65,66 Under normal conditions, the protein crystalline (bg, gC types) assures lens and cornea transparency and is also necessary for refractive power. 67,68 Therefore, it is expected that mutations in the crystalline gene are linked to cataract formation in humans.…”

“…Mutation of the CRYBA2 gene, a member of bg crystalline causes congenital cataracts. 66 Furthermore, mutation in CRYGC gene (gC-crystalline) makes the lens less thermally stable and increases the risk of lens opacity when exposed to heat and UV radiation and ultimately also leads to cataract formation. 65 Similarly the cloche zebrafish mutant displays cataracts associated with a defect in gamma crystalline induced by alpha A crystalline.…”

Exome sequencing identifies novel and recurrent mutations in GJA8 and CRYGD associated with inherited cataract

“…The iron response element (IRE) of FTL is located in the 5′-UTR (untranslated region) and was not covered by capture probes. In addition, coverage of the single exons that code for FOXE3 and MAF was incomplete as previously reported [13]. We excluded mutations in all three missing gene regions by Sanger sequencing of an affected member of each family essentially as described [13,14].…”

“…In addition, coverage of the single exons that code for FOXE3 and MAF was incomplete as previously reported [13]. We excluded mutations in all three missing gene regions by Sanger sequencing of an affected member of each family essentially as described [13,14]. Collectively, from the nine exomes sequenced, 112 variants were identified in 32 of the 39 candidate genes (Additional file 3).…”