Deafness, Autosomal Recessive 9

A number sign (#) is used with this entry because autosomal recessive deafness-9 (DFNB9) and auditory neuropathy-1 (AUNB1) are caused by homozygous or compound heterozygous mutation in the gene encoding otoferlin (OTOF; 603681) on chromosome 2p23.

Clinical Features

Chaib et al. (1996) reported a consanguineous Lebanese family with autosomal recessive sensorineural nonsyndromic hearing loss. For affected children, deafness was noted by their parents at birth or before the age of 2 years. None of the children had balance problems, and there was no evidence for an acquired risk factor predisposing to hearing loss. Audiometry showed no response at 100 dB for frequencies superior to 1,000 Hz in all affected subjects. In affected children, no auditory brainstem response was observed up to 100 dB. In the parents, who were obligate carrier heterozygotes, audiometric tests were normal.

Nonsyndromic Recessive Auditory Neuropathy

Varga et al. (2003) defined a specific type of deafness, termed 'nonsyndromic recessive auditory neuropathy' (NSRAN). Affected patients have hearing loss based on pure-tone audiometry and auditory brainstem response test results, which measure the overall auditory pathway, but have a normal otoacoustic emissions (OAE) test, which detects responses of the outer hair cells to environmental sound. Subjects with NSRAN can have varying degrees of hearing loss with poor speech reception out of proportion to the degree of hearing loss. Most subjects with NSRAN are not helped by hearing aids, but may be helped by cochlear implants. Varga et al. (2003) reported 9 affected children from 4 families with NSRAN.

Tekin et al. (2005) reported 3 Turkish sibs, born of consanguineous parents, with NSRAN confirmed by genetic analysis (603681.0010). All 3 children had severe to profound prelingual sensorineural hearing loss. Acoustic middle ear reflexes were absent in the 2 older children, and all 3 children had absent auditory brainstem responses. All 3 sibs showed U- or bowl-shaped audiometric configurations at ages 8, 7, and 6 years, respectively, with the most severe hearing loss in the 500-2,000 Hz frequency range. Otoacoustic emissions were present in 2 children, consistent with auditory neuropathy. OAE were absent in 1 child, although emissions may have disappeared through damage caused by several years of hearing aid use. Tekin et al. (2005) suggested that auditory neuropathy is the only phenotypic manifestation of mutations in the OTOF gene.

Varga et al. (2006) summarized findings in auditory neuropathy. The term 'auditory neuropathy' was first coined by Starr et al. (1996). Auditory neuropathy/auditory dys-synchrony (AN/AD) is a unique type of hearing loss diagnosed when tympanographs are normal and acoustic reflexes (AR) and auditory brainstem response (ABR) are absent or severely abnormal, but outer hair cell (OHC) function is normal as indicated by the presence of otoacoustic emissions (OAE) and/or cochlear microphonics (CM). These test results indicate that the auditory pathway up to and including the OHC is functioning but the auditory signal is not transmitted to the brainstem, suggesting that the lesion lies at the level of the inner hair cells (IHC), the IHC synapse to the afferent nerve fibers, or the auditory nerve itself. Individuals with this disorder can have various degrees of hearing loss as measured by pure tone audiometry. They generally have disproportionately poor speech understanding. In contrast to individuals with non-AN/AD hearing loss, hearing aids may provide little help in speech understanding in most individuals with AN/AD. Cochlear implantation has been shown to help the speech understanding in some cases of AN/AD, but others have not had favorable results.

Nonsyndromic Recessive Auditory Neuropathy, Temperature-Sensitive

Varga et al. (2006) reported 2 sibs with a temperature-sensitive auditory neuropathy phenotype. Audiogram of the proband when afebrile showed mild low frequency hearing loss, and speech comprehension was below the 10th percentile for both quiet and noise. Tympanometry was normal and AR were absent. ABR was abnormal, but CM were present. On 2 occasions testing was performed during febrile illness. At a temperature of 38.1 degrees C, her pure tone thresholds decreased to profound deafness in the low frequencies, rising to severe hearing loss in the high frequencies. Speech awareness threshold was 80 dB hearing level (HL), but she was unable to repeat any of the test spondee words. Tympanometry and OAE were normal, but AR and ABR were absent. With a temperature of 37.8 degrees C she was tested again and showed a mild to moderate hearing loss and zero speech comprehension. The following day her auditory functions returned to baseline after the fever abated. The proband had reported to her parents that her hearing becomes affected suddenly when she is febrile. Her brother was similarly affected. Varga et al. (2006) found that these sibs carried an ile515-to-thr mutation in otoferlin (603681.0001). The mutation was heterozygous in the unaffected father; the mutation in the mother and on the maternal allele of the sibs was unknown at the time of the report. Clinical features of the family had been reported by Starr et al. (1998).

Matsunaga et al. (2012) reported a 26-year-old Japanese man, born of consanguineous parents, with temperature-sensitive auditory neuropathy associated with a homozygous mutation in the OTOF gene (G541S; 603681.0013) that only affected the long isoform. The patient complained of difficulty in understanding conversation and reported that his hearing deteriorated when he became febrile or was exposed to loud noise. Pure-tone audiometry when he was afebrile revealed mild hearing loss with a flat configuration.

Mapping

In a consanguineous family living in an isolated region of Lebanon, Chaib et al. (1996) demonstrated linkage of an autosomal form of neurosensory deafness to markers on 2p23-p22. A maximum lod score of 8.03 was detected with a new polymorphic marker, D2S2144. Observed recombinants and homozygosity mapping defined a maximum interval of 2 cM for this gene which lies between D2S2303 and D2S174.

Leal et al. (1998) found linkage to the same region of 2p23-p22 in a highly consanguineous kindred from eastern Turkey. Affected members had prelingual profound hearing loss involving all the frequencies. The genetic map generated by the authors suggested that the region for DFNB9 is less than 1.08 cM (95% CI = 0-2.59 cM).

In 4 families with NSRAN, Varga et al. (2003) found linkage to the OTOF gene on chromosome 2p23.

Molecular Genetics

In all members affected with DFNB9 in 4 unrelated Lebanese kindreds, Yasunaga et al. (1999) identified a missense mutation in the OTOF gene (603681.0001).

In 1 Cuban family, 2 Spanish families, and 8 sporadic Spanish patients with nonsyndromic sensorineural hearing loss, Migliosi et al. (2002) identified a gln829-to-ter mutation in exon 22 of the OTOF gene (Q829X; 603681.0004). Migliosi et al. (2002) determined that the Q829X mutation was responsible for 4.4% of recessive familial or sporadic cases of deafness in the Spanish population, and presented evidence for a founder effect.

In 3 of 4 families with NSRAN, Varga et al. (2003) identified 4 mutations in the OTOF gene (603681.0006-603681.0009). Two of the families had heterozygous mutations. Varga et al. (2003) noted that previous publications on patients with DFNB9 did not report testing for outer hair cell functioning; thus, it is unclear whether there is a consistent phenotype for hearing loss caused by mutation in the OTOF gene.

Varga et al. (2006) described an allele of the OTOF gene that appeared to be associated with temperature-sensitive auditory neuropathy (603681.0011).

Romanos et al. (2009) identified 10 different mutations in the OTOF gene, including 6 novel mutations, in affected individuals from 8 Brazilian families with hearing loss or auditory neuropathy. The common Spanish Q829X mutation was not identified in a larger sample of 342 deaf individuals, indicating that it is not a common cause of deafness in Brazil.

Population Genetics

Choi et al. (2009) screened a cohort of 557 large Pakistani families segregating recessive severe to profound prelingual-onset deafness and identified 13 families with linkage to markers for DFNB9; analysis of the OTOF gene revealed probable pathogenic sequence variants in affected individuals from all 13 families. OTOF mutations thus accounted for deafness in 13 (2.3%) of 557 Pakistani families, which Choi et al. (2009) stated was not significantly different from the prevalence found in other populations.

Matsunaga et al. (2012) identified an R1939Q (603681.0012) mutation in the OTOF gene, in 13 (56.5%) of 23 Japanese patients with early-onset auditory neuropathy. Seven patients were homozygous for the mutation, 4 were compound heterozygous for R1939Q and a truncating or splice site mutation in OTOF, 1 was compound heterozygous for R1939Q and a nontruncating mutation in OTOF, and 1 was heterozygous for the R1939Q mutation. Haplotype analysis indicated a founder effect for the R1939Q mutation. Those who were homozygous for R1939Q or compound heterozygous for R1939Q and a truncating mutation had a consistent and severe phenotype, whereas the patient who was compound heterozygous for R1939Q and a nontruncating mutation had a less severe phenotype, with moderate hearing loss at age 29 years and sloping audiograms. The findings suggested that the R1939Q variant likely causes a severe impairment of protein function, and that, in general, truncating mutations cause a more severe phenotype than nontruncating mutations.

Animal Model

Roux et al. (2006) found that Otof -/- mice were profoundly deaf. Exocytosis in Otof -/- auditory inner hair cells was almost completely abolished, despite normal ribbon synapse morphogenesis and Ca(2+) current. Roux et al. (2006) concluded that OTOF is essential for a late step of synaptic vesicle exocytosis and may act as the major Ca(2+) sensor triggering membrane fusion at the auditory inner hair cell ribbon synapse.

Nomenclature

Chaib et al. (1996) referred to the deafness locus that they located on 2p23-p22 as DFNB6; however, this designation had been preempted for the locus defined by Fukushima et al. (1995) (see 600971). Therefore, the 2p23-p22 locus is referred to here as DFNB9.