OSBPL2 – Autosomal dominant nonsyndromic hearing loss

The oxysterol-binding protein-like 2 (OSBPL2) gene has been implicated in autosomal dominant nonsyndromic hearing loss (Autosomal dominant nonsyndromic hearing loss). Initial evidence arose from a seven-generation Chinese pedigree segregating progressive sensorineural hearing impairment.

Whole-exome sequencing in three affected family members identified a heterozygous frameshift variant, c.153_154delCT (p.Gln53ArgfsTer100), in OSBPL2 that cosegregated with hearing loss. Subsequent Sanger sequencing confirmed the variant in 25 affected relatives across seven generations (PMID:25077649). An independent c.583C>A (p.Leu195Met) missense variant was identified in a sporadic case, supporting replication of the gene–disease association (PMID:25077649).

Robust segregation analysis demonstrated the truncating OSBPL2 allele in 25 affected individuals, with 22 additional relatives beyond the probands showing variant co-segregation. This pedigree provides strong family-based evidence for autosomal dominant inheritance, with no reports of phenocopies or incomplete penetrance (PMID:25077649).

Variant spectrum to date includes one recurrent frameshift (c.153_154delCT (p.Gln53ArgfsTer100)) and one missense change (c.583C>A (p.Leu195Met)). The truncating mutation is predicted to lead to premature protein termination and loss of function, whereas the missense substitution affects a conserved residue within the lipid-binding domain.

Structural modeling and in silico analyses support a deleterious impact of the p.Gln53ArgfsTer100 variant on OSBPL2 folding and ligand binding, consistent with a haploinsufficiency mechanism in cochlear hair cells (PMID:25077649). No functional rescue studies have yet been reported.

Integration of genetic and preliminary functional data yields a Moderate level of clinical validity. OSBPL2 sequencing should be considered in autosomal dominant hearing loss panels to facilitate diagnosis and family counseling.

References

• Genetics in medicine • 2015 • Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing. PMID:25077649

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