Mutations in the OTOF gene in Taiwanese patients with auditory neuropathy

Mutations in the OTOF gene have been found to be common causes of auditory neuropathy (AN) in Caucasians. However, the prevalence and spectrum of OTOF mutations in other populations have been inadequately documented. To explore the genetic characteristics of East Asian patients with AN, we screened for mutations in the OTOF gene by direct sequencing in 22 unrelated Taiwanese AN families (including 2 multiplex and 20 simplex families) and looked for genotype-phenotype correlations. Among the probands of the 22 AN families, a novel OTOF variant, p.E1700Q (c.5098G→C), was identified in 5 probands (23%), including 4 homozygotes and 1 heterozygote. By using restriction fragment length polymorphism to screen another 500 unrelated patients with idiopathic sensorineural hearing impairment, we further identified 1 p.E1700Q homozygote who also had clinical features compatible with AN. Furthermore, p.E1700Q was not identified in a panel of 100 normal controls, it cosegregated with the AN phenotype in the pedigrees, and the p.E1700 residue is evolutionarily conserved, consistent with its pathogenicity for AN. The associated audiologic features included progressive, prelingual, bilateral moderate-to-profound sensorineural hearing loss with a flat-type audiogram configuration. After genotyping single-nucleotide polymorphisms in the vicinity of p.E1700Q, we found that OTOF alleles with p.E1700Q shared a common haplotype, suggesting a founder effect for p.E1700Q. The predominance of the p.E1700Q mutation and the evidence of its founder effect indicate a distinct OTOF mutation spectrum in Taiwanese patients with AN.