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

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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.

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Acknowledgments

The authors gratefully acknowledge the patients and their families for their participation in research studies. This work was supported by the National Institutes of Health awards R01EY015518, R21DC010912 and funds provided by the Children’s Hospital of Wisconsin (EVS), 1UL1RR031973 from the Clinical and Translational Science Award (CTSA) program, and was supported in part by Research to Prevent Blindness, Inc., New York, NY (DPH and DC); the authors are also thankful to Elena A. Sorokina for cloning of zebrafish cryba2 gene sequences and thoughtful discussions.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

All experiments described comply with the current laws of the United States of America.

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Correspondence to Elena V. Semina.

Electronic supplementary material

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Online Resource 1. Pedigrees of 23 families affected with hereditary cataract and examined in this study. Probands are indicated with an arrow; black symbol indicates congenital or juvenile cataract, gray symbol indicates adult-onset cataract (age of diagnosis indicated under the symbol); individuals included in variant/mutation cosegregation analyses are marked with asterisks; if a causative mutation was identified in the family, the gene is listed in parentheses.

Online Resource 2. Summary of WES data for all probands included in this study.

Online Resource 3. List of known cataract genes reviewed in this study.

Online Resource 4. Rare and novel variants determined to be non-causative.

Supplementary material 1 (PDF 259 kb)

Supplementary material 2 (PDF 99 kb)

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Reis, L.M., Tyler, R.C., Muheisen, S. et al. Whole exome sequencing in dominant cataract identifies a new causative factor, CRYBA2, and a variety of novel alleles in known genes. Hum Genet 132, 761–770 (2013). https://doi.org/10.1007/s00439-013-1289-0

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  • DOI: https://doi.org/10.1007/s00439-013-1289-0

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