GJB2 (DFNB1A)

GJB2 encodes the gap junction protein Connexin 26, a critical component of the intracellular pathway for potassium cycling between the endolymph and perilymph of the cochlea. Mutations in GJB2 account for up to 50% of patients with nonsyndromic AR SNHL. Hearing loss from GJB2 was first described in 1997, and since then, routine DNA sequencing of the coding region of GJB2 reported across the world has demonstrated interesting patterns of genotypes across populations. Particularly prevalent mutant alleles include 35delG, found in Europe and the Middle East (particularly regions surrounding the Mediterranean); 235delC, found in East Asia, V37I, common in Southeast Asia; and W24X, common in India.

Inactivating truncating mutations in GJB2 (stop codons or frameshift mutations, such as small insertions/deletions) are generally associated with severe-to-profound SNHL. In contrast, noninactivating nontruncating mutations in GJB2 (base changes that result in single amino acid substitutions) are associated with moderate or even mild SNHL. The large, noncoding deletions involving the adjacent GJB6 gene, which encodes for the protein Connexin 30, are thought to cause hearing loss through their effects on GJB2 expression, and not through the effects on GJB6.

Table 2 lists some of the more common truncating and nontruncating GJB2 mutations. The number of discovered mutations continues to increase over time, and a more comprehensive updated list can be found at the Connexin-deafness homepage ( http://www.crg.es/deafness ). Patients with 2 truncating mutations tend to have severe-to-profound hearing loss, while those with a truncating and nontruncating mutation have more moderate hearing loss, and those with 2 nontruncating mutations tend to have mild hearing loss. However, those with 2 nontruncating mutations, especially those homozygous for V37I, had up to a 39% to 50% rate of progression of hearing loss. GJB2 sequencing, along with computed tomography (CT)/MRI of the temporal bone remain 2 of the highest yield diagnostic evaluations for children presenting with SNHL.

Although GBJ2 hearing loss is thought to be AR, thus requiring 2 mutations to result in the hearing loss phenotype, meta-analysis of carrier rates between normal hearing and hearing loss populations demonstrates significantly increased rates of truncating mutations in the hearing loss populations, suggesting an unidentified genetic factor contributing to hearing loss in some heterozygote carriers, or alternatively, that there is a carrier phenotype that is penetrant in a small proportion of carriers. Data from 52,715 normal-hearing controls from 115 studies across 55 countries reveal a worldwide carrier rate of 1.5% for 35delG, ranging from 0% in multiple countries to 5.7% in Belarus. The carrier rate for V37I among 20,866 controls across 72 studies from 26 countries is 2.5%, ranging from 0% to as high as 16.7% in Thailand.

SLC26A4 (DFNB4)

SLC26A4 encodes a chloride and iodide anion transporter and is the second most common nonsyndromic AR SNHL after GJB2. Mutations in SLC26A4 may also cause syndromic SNHL, in the form of Pendred syndrome. Because goiter generally does not become apparent until puberty, this form of SNHL characteristically initially presents as nonsyndromic. Not all patients with biallelic SLC26A4 mutations will go on to develop goiter, and thus they will continue to demonstrate true DFNB4 nonsyndromic SNHL.

Many patients with SLC26A4 may demonstrate enlarged vestibular aqueducts (EVA) on CT scan, or enlarged endolymphatic ducts and sacs on MRI. This radiologic finding has important implications for management, because patients with EVA can experience sudden and dramatic hearing loss following minor head trauma. Children with biallelic SLC26A4 mutations are at high risk of developing goiter and hypothyroidism following puberty. Also, about 30% of children with Pendred syndrome have symptomatic vestibular problems, and about another 30% show reduced vestibular function on formal testing.

MYO15A (DFNB3)

Mutations in MYO15A cause congenital severe-to-profound SNHL. Myosin XV is thought to be necessary for actin organization in hair cells and normal stereocilia tip link function.

OTOF (DFNB9)

OTOF encodes otoferlin, a protein essential for synaptic vesicle exocytosis, and may act as the major calcium sensor triggering membrane fusion at the inner hair cell ribbon synapse. Mutations in OTOF result in hearing impairment characterized by auditory neuropathy/auditory dissynchrony (AN/AD), which is diagnosed when auditory brainstem responses (ABRs) are absent or severely abnormal, but outer hair cell (OHC) function is normal as indicated by the presence of otoacoustic emissions (OAEs) and strong cochlear microphonic. Other nongenetic causes of AN/AD include risk factors such as prematurity, hypoxia, and hyperbilirubinemia. In a Japanese study of AN/AD without environmental risk factors, over 56% of cases had OTOF mutations. Individuals with this disorder can have various degrees of hearing loss by pure tone behavioral audiometry; however they generally have disproportionately poor speech understanding. In contrast to individuals with non-AN/AD SNHL, hearing aids often provide only limited benefit to speech understanding in most individuals with AN/AD. Cochlear implantation has been shown to help the speech understanding in some children with AN/AD from mutations in OTOF.

CDH23 (DFNB12)

Mutations in the gene encoding cadherin-23 (CDH23) result in Usher syndrome type 1D, characterized by SNHL, retinitis pigmentosa, and vestibular dysfunction. The same genetic locus, DFNB12, is the site of a form of nonsyndromic AR SNHL resulting in a moderate-to-profound progressive SNHL.

TMC1 (DFNB7/11)

TMC1 encodes a transmembrane protein that is required for the normal function of cochlear hair cells. TMC1 appears to be a common cause of recessive deafness in consanguineous Indian, Pakistani, Turkish, and Tunisian families. Recessive mutations of TMC1 all result in a prelingual severe-to-profound SNHL.