Identification of a genetic variant underlying familial cases of recurrent benign paroxysmal positional vertigo

In this study, we performed whole exome sequencing [including untranslated regions (UTRs)] of 12 families and Sanger sequencing of additional 30 families with recurrent BPPV in Caucasians from the United States (US) Midwest region, to identify the genetic variant s responsible for heightened susceptibility to BPPV. Fifty non-BPPV families were included as controls.In silico and experimental analyses of candidate variants show that an insertion variant rs113784532 (frameshift causing truncation) in the neural cadherin genePCDHGA10 (protocadherin-gamma A10) is an exceedingly strong candidate (p = 1.80x10-4 vs. sample controls; p = 5.85x10-19 vs. ExAC data; p = 4.9x10-3 vs. NHLBI exome data). The mutant protein forms large aggregates in BPPV samples even at young ages, and affected subjects carrying this variant have an earlier onset of the condition than those without [average 44.0 ±14.0 (n = 16) versus 54.4±16.1 (n = 36) years old, p = 0.054]. In both human and mouse inner ear tissues, PCDHGA10 is expressed in ganglia, hair cells and vestibular transitional epithelia. Fluorescent RNAin situ hybridization using mouse inner ear tissues shows that expression increases with age. In summary, our data show that a variant in thePCDHGA10 gene may be involved in causing or aggravating some familial cases of recurrent idiopathic BPPV.
Source: PLoS One - Category: Biomedical Science Authors: Source Type: research