title: 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.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Samer
authors.initials: S
authors.lastname: Khateb
authors.forename: Lina
authors.initials: L
authors.lastname: Zelinger
authors.forename: Tamar
authors.initials: T
authors.lastname: Ben-Yosef
authors.forename: Saul
authors.initials: S
authors.lastname: Merin
authors.forename: Ornit
authors.initials: O
authors.lastname: Crystal-Shalit
authors.forename: Menachem
authors.initials: M
authors.lastname: Gross
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017668:Age of Onset; D017398:Alternative Splicing / Q000235:genetics; D001299:Audiometry; D001483:Base Sequence; D018797:Cell Cycle Proteins; D020090:Chromosome Segregation / Q000235:genetics; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D016368:Frameshift Mutation / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D034381:Hearing Loss / Q000150:complications / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007557:Israel / Q000453:epidemiology; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012174:Retinitis Pigmentosa / Q000150:complications / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C118970:USH1C protein, human