A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy

Abstract

Autosomal recessive nonsyndromic hearing impairment (NSHI) is a heterogeneous condition, for which 53 genetic loci have been reported, and 29 genes have been identified to date. One of these, OTOF, encodes otoferlin, a membrane-anchored calcium-binding protein that plays a role in the exocytosis of synaptic vesicles at the auditory inner hair cell ribbon synapse. We have investigated the prevalence and spectrum of deafness-causing mutations in the OTOF gene. Cohorts of 708 Spanish, 83 Colombian, and 30 Argentinean unrelated subjects with autosomal recessive NSHI were screened for the common p.Gln829X mutation. In compound heterozygotes, the second mutant allele was identified by DNA sequencing. In total, 23 Spanish, two Colombian and two Argentinean subjects were shown to carry two mutant alleles of OTOF. Of these, one Colombian and 13 Spanish subjects presented with auditory neuropathy. In addition, a cohort of 20 unrelated subjects with a diagnosis of auditory neuropathy, from several countries, was screened for mutations in OTOF by DNA sequencing. A total of 11 of these subjects were shown to carry two mutant alleles of OTOF. In total, 18 pathogenic and four neutral novel alleles of the OTOF gene were identified. Haplotype analysis for markers close to OTOF suggests a common founder for the novel c.2905_2923delinsCTCCGAGCGCA mutation, frequently found in Argentina. Our results confirm that mutation of the OTOF gene correlates with a phenotype of prelingual, profound NSHI, and indicate that OTOF mutations are a major cause of inherited auditory neuropathy.

Novel OTOF mutations in Brazilian patients with auditory neuropathy

“…A second mutation was not found. The clinical findings of patient 2, who presents AN, were detailed in Favero et al 24 An indel mutation, c.2905-2923del19ins11, described by RodriguezBallesteros et al, 25 was detected in heterozygosis in family 1. This family had a Lebanese origin and both affected children had absent ABR and OAEs.…”

Auditory neuropathy — neural and synaptic mechanisms

“…For example, the predominant 'Spanish muta tion' (Gln829Ter, resulting in truncation) in OTOF was found in 8% of the congenital nonsyndromic deaf population with autosomal recessive inheritance of Spanish descent, and is the thirdmost common cause for prelingual deafness 10 . By contrast, a mutation in SLC17A8 -which encodes vesicular glutamate trans porter 3 (VGluT3) -has been described in only one large family of Czech descent 11 .…”

Audibility, speech perception and processing of temporal cues in ribbon synaptic disorders due to OTOF mutations

“…The currently-known spectrum of sequence variants of the OTOF gene includes more than 90 pathogenic mutations and over 50 neutral variants (Mahdieh et al, 2012;Rodríguez-Ballesteros et al, 2008). Pathogenic variants are responsible for the DFNB9 type of autosomal recessive non-syndromic hearing impairment (Yasunaga et al, 1999).…”

“…These mutations have been found in very different proportions in cohorts of subjects from several countries, ranging from about 5% in some Chinese and Korean studies, through 50e60% in studies from the USA, Brazil and Japan, to 86% in Spanish cohorts (Bae et al, 2013;Chiu et al, 2010;Jin et al, 2014;Matsunaga et al, 2012;Rodríguez-Ballesteros et al, 2008;Romanos et al, 2009;Varga et al, 2006;Wang et al, 2010). This wide range of frequencies may reflect an actual diversity between populations, as exemplified by the very high frequency seen in the Spanish population, which is probably related to a genetic founder effect for a single, very frequent mutation.…”