Purpose: Various forms of hearing loss have genetic causes, but many of the responsible genes have not yet been identified. Here, we describe a large seven-generation Chinese family with autosomal dominant nonsyndromic hearing loss that has been excluded as being caused by known deafness gene mutations associated with autosomal dominant nonsyndromic hearing loss with the aim of identifying a novel causative gene involved in deafness.
Methods: Whole-exome sequencing was conducted in three affected family members, and cosegregation analysis was performed on other members of the family.
Results: Whole-exome sequencing and subsequent segregation analysis identified a heterozygous frameshift mutation (c.153_154delCT, p.Gln53Argfs*100) in the oxysterol binding protein-like 2 (OSBPL2) gene in 25 affected family members. The deletion mutation is predicted to lead to premature truncation of the OSBPL2 protein. Modeling and structure-based analysis support the theory that this gene deletion is functionally deleterious. Our finding was further confirmed by the detection of another missense mutation, a c.583C>A transversion (p.Leu195Met) in exon 7 of OSBPL2, in an additional sporadic case of deafness.
Conclusion: Based on this study, OSBPL2 was identified as an excellent novel candidate gene for autosomal dominant nonsyndromic hearing loss; this study is the first to implicate OSBPL2 mutations in autosomal dominant nonsyndromic hearing loss.