Exome sequencing identifies a founder frameshift mutation in an alternative exon of USH1C as the cause of autosomal recessive retinitis pigmentosa with late-onset hearing loss

PLoS One. 2012;7(12):e51566. doi: 10.1371/journal.pone.0051566. Epub 2012 Dec 12.


We used a combined approach of homozygosity mapping and whole exome sequencing (WES) to search for the genetic cause of autosomal recessive retinitis pigmentosa (arRP) in families of Yemenite Jewish origin. Homozygosity mapping of two arRP Yemenite Jewish families revealed a few homozygous regions. A subsequent WES analysis of the two index cases revealed a shared homozygous novel nucleotide deletion (c.1220delG) leading to a frameshift (p.Gly407Glufs*56) in an alternative exon (#15) of USH1C. Screening of additional Yemenite Jewish patients revealed a total of 16 homozygous RP patients (with a carrier frequency of 0.008 in controls). Funduscopic and electroretinography findings were within the spectrum of typical RP. While other USH1C mutations usually cause Usher type I (including RP, vestibular dysfunction and congenital deafness), audiometric screening of 10 patients who are homozygous for c.1220delG revealed that patients under 40 years of age had normal hearing while older patients showed mild to severe high tone sensorineural hearing loss. This is the first report of a mutation in a known USH1 gene that causes late onset rather than congenital sensorineural hearing loss. The c.1220delG mutation of USH1C accounts for 23% of RP among Yemenite Jewish patients in our cohort.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Age of Onset
  • Alternative Splicing / genetics
  • Audiometry
  • Base Sequence
  • Cell Cycle Proteins
  • Chromosome Segregation / genetics
  • Cytoskeletal Proteins
  • DNA Mutational Analysis
  • Exome / genetics*
  • Exons / genetics*
  • Female
  • Founder Effect*
  • Frameshift Mutation / genetics*
  • Genes, Recessive / genetics
  • Genome, Human / genetics
  • Hearing Loss / complications
  • Hearing Loss / genetics*
  • Homozygote
  • Humans
  • Israel / epidemiology
  • Male
  • Molecular Sequence Data
  • Pedigree
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Retinitis Pigmentosa / complications
  • Retinitis Pigmentosa / genetics*
  • Sequence Analysis, DNA


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • USH1C protein, human

Grants and funding

This study was financially supported by the Foundation Fighting Blindness USA (BR-GE-0510-0490-HUJ to DS), by the legacy heritage biomedical program of the Israeli Science Foundation (grant number 612/09 to DS and TBY), and the Yedidut 1 research grant (to EB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.