Mutations of the gene encoding otogelin are a cause of autosomal-recessive nonsyndromic moderate hearing impairment.

Already 40 genes have been identified for autosomal-recessive nonsyndromic hearing impairment (arNSHI); however, many more genes are still to be identified. In a Dutch family segregating arNSHI, homozygosity mapping revealed a 2.4 Mb homozygous region on chromosome 11 in p15.1-15.2, which partially overlapped with the previously described DFNB18 locus. However, no putative pathogenic variants were found in USH1C, the gene mutated in DFNB18 hearing impairment. The homozygous region contained 12 additional annotated genes including OTOG, the gene encoding otogelin, a component of the tectorial membrane. It is thought that otogelin contributes to the stability and strength of this membrane through interaction or stabilization of its constituent fibers. The murine orthologous gene was already known to cause hearing loss when defective. Analysis of OTOG in the Dutch family revealed a homozygous 1 bp deletion, c.5508delC, which leads to a shift in the reading frame and a premature stop codon, p.Ala1838ProfsX31. Further screening of 60 unrelated probands from Spanish arNSHI families detected compound heterozygous OTOG mutations in one family, c.6347C>T (p.Pro2116Leu) and c. 6559C>T (p.Arg2187X). The missense mutation p.Pro2116Leu affects a highly conserved residue in the fourth von Willebrand factor type D domain of otogelin. The subjects with OTOG mutations have a moderate hearing impairment, which can be associated with vestibular dysfunction. The flat to shallow "U" or slightly downsloping shaped audiograms closely resembled audiograms of individuals with recessive mutations in the gene encoding α-tectorin, another component of the tectorial membrane. This distinctive phenotype may represent a clue to orientate the molecular diagnosis.

Audiovestibular Manifestations in Patients with Primary Raynaud's Phenomenon and Raynaud's Phenomenon Secondary to Systemic Sclerosis.

OBJECTIVES: To address the prevalence of audiovestibular disorders in patients with primary Raynaud's Phenomenon (RP). A series of patients with primary RP and secondary RP in the context of systemic sclerosis (SSc) were compared with healthy controls. METHODS: A prospective multicenter observational cross-sectional study was conducted in several Otolaryngology and Rheumatology Divisions of tertiary referral hospitals, recruiting 57 patients with RP and 57 age- and gender-matched controls. Twenty patients were classified as primary RP when unrelated to any other conditions and 37 patients who met the 2013 ACR/EULAR classification criteria for SSc were classified as having secondary RP associated with SSc. Audiometric and vestibular testing (vHIT), clinical sensory integration and balance testing (CTSIB), and Computerized Dynamic Posturography (CDP) were performed. RESULTS: As significant differences were found in the age of the two study groups, primary and secondary RP, no comparisons were made between both groups of RP but only with their control groups. No sensorineural hearing loss (SNHL) was recorded in any of our patients with primary RP and no differences were found in the voice audiometry tests with respect to controls. Four of 37 (10.8%) secondary RP patients presented SNHL. Those with SNHL were 7.03 times more likely to have a secondary RP than controls (p < 0.001). The audiometric curve revealed high-frequency hearing loss in 4 patients with RP secondary to SSc, and statistically significant differences were achieved when RP secondary was compared to controls in vHIT gain, caloric test, CTSIB, and CDP. CONCLUSIONS: Unlike patients with RP secondary to SSc, patients with primary RP do not show audiovestibular abnormalities. Regarding audiovestibular manifestations, primary RP can be considered a different condition than secondary RP.