Human Genetics

, Volume 132, Issue 7, pp 761–770

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

  • Linda M. Reis
  • Rebecca C. Tyler
  • Sanaa Muheisen
  • Victor Raggio
  • Leonardo Salviati
  • Dennis P. Han
  • Deborah Costakos
  • Hagith Yonath
  • Sarah Hall
  • Patricia Power
  • Elena V. Semina
Original Investigation

DOI: 10.1007/s00439-013-1289-0

Cite this article as:
Reis, L.M., Tyler, R.C., Muheisen, S. et al. Hum Genet (2013) 132: 761. doi:10.1007/s00439-013-1289-0

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.

Supplementary material

439_2013_1289_MOESM1_ESM.pdf (259 kb)
Supplementary material 1 (PDF 259 kb)
439_2013_1289_MOESM2_ESM.pdf (99 kb)
Supplementary material 2 (PDF 99 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Linda M. Reis
    • 1
  • Rebecca C. Tyler
    • 1
  • Sanaa Muheisen
    • 1
  • Victor Raggio
    • 2
  • Leonardo Salviati
    • 3
  • Dennis P. Han
    • 4
  • Deborah Costakos
    • 4
  • Hagith Yonath
    • 5
  • Sarah Hall
    • 6
  • Patricia Power
    • 7
  • Elena V. Semina
    • 1
    • 8
  1. 1.Department of Pediatrics and Children’s Research InstituteMedical College of WisconsinMilwaukeeUSA
  2. 2.Genetics DepartmentSchool of MedicineMontevideoUruguay
  3. 3.Department of Woman and Child HealthUniversity of PadovaPaduaItaly
  4. 4.Department of OphthalmologyMedical College of WisconsinMilwaukeeUSA
  5. 5.Sheba Medical Center, Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  6. 6.Kadlec Regional Medical CenterRichlandUSA
  7. 7.Department of Medical GeneticsUniversity of British ColumbiaVancouverCanada
  8. 8.Department of Cell Biology, Neurobiology and AnatomyMedical College of WisconsinMilwaukeeUSA