Suzanne de Bruijn

123 A RIPOR2 deletion is a frequent cause of adult-onset hearing loss index cases and discordant alleles were seen for SNP rs6901322 (Chr6: 24,583,804) that is located between D6S2439 and D6S1554. This SNP was found in homozygous state in subject IV:20 (W97-056), but was absent in the index cases of familiesW02-016 (III:9) and W18-0473. Based on these results, the shared haplotype is delimited by SNP rs6901322 at the telomeric side and comprises a region of 0.713 Mb. Genome sequencing in two members of family W97-056 (IV:25 and III:22) excluded potentially causative CNVs or other structural variants that are present within the shared chromosomal region. The c.1696_1707del RIPOR2 variant is not associated with vestibular dysfunction Four of 64 subjects with the RIPOR2 variant had vestibular complaints. Subjects III:1, III:9, IV:1 (W02-016) and the index cases of familyW18-0472 reported infrequent vertigo attacks, complaints after cochlear implant surgery, a diagnosis of benign paroxysmal positional vertigo and migrainous vertigo, respectively ( Table S3 ). Vestibular testing was randomly performed in 9 subjects with the RIPOR2 variant, aged 29 to 71 years, and included the abovementioned subjects III:1 and III:9 of familyW02-016. No abnormalities were found, except for a mild hyporeflexia in subject III:1 of family W02-016 ( Table S4 ), which is appropriate for the subject’s age of 71 years. Based on these results, we conclude that c.1696_1707del RIPOR2 is not associated with vestibular dysfunction. This is in line with the lack of vestibular dysfunction in Ripor2 -/- mice despite expression of the gene in the vestibular organ of wildtype mice. 15 Also, humans with recessively inherited HL caused by a homozygous loss-of-function defect in RIPOR2 , did not report balance problems, vertigo or dizziness but absence of a vestibular phenotype was not confirmed by objective vestibular testing. 16