Genetics of Hearing Loss—Nonsyndromic




Key points








  • Autosomal-recessive (AR) nonsyndromic hearing loss is usually prelingual and frequently results in severe hearing loss, although milder and progressive hearing loss forms also exist. GJB2 and SLC26A4 are the 2 most common AR genes.



  • Autosomal-dominant (AD) nonsyndromic hearing loss is often postlingual and progressive. No single gene accounts for any significant proportion of AD hearing loss.



  • High-throughput sequencing techniques, also called next-generation sequencing (NGS) or massively parallel sequencing (MPS), now allow comprehensive testing of all known deafness-associated genes in a child presenting with congenital hearing loss.




Hearing loss is the most common congenital sensory impairment, affecting 1 in 500 newborns and 1 in 300 children by the age of 4. Approximately 1 in 1000 newborns has genetically inherited hearing loss. Nonsyndromic etiologies account for 70% of genetic hearing loss, with only 30% being syndromic and demonstrating other clinical findings.


Autosomal-recessive (AR) inheritance accounts for 80% of nonsyndromic genetic hearing loss and is usually prelingual. Autosomal-dominant (AD) inheritance accounts for most of the other 20% and is more often postlingual. AR nonsyndromic hearing loss (designated “DFNB#”) most frequently results in severe hearing loss, which presents early, whereas AD nonsyndromic hearing loss (designated “DFNA#”) typically results in progressive sensorineural hearing loss (SNHL) with variable severity, which begins at 10 to 40 years. Patients with mitochondrial inheritance tend to develop progressive SNHL, which begins at 5 to 50 years, and the degree of hearing loss is variable. X-linked (designated “DFNX#”) and mitochondrial inheritance account for only 1% to 2% of nonsyndromic hearing loss.


Nonsyndromic SNHL may be caused by mutations in any one of an increasing number of identified genes. Currently, over 100 genes for SNHL have been mapped, some listed on Table 1 (a more comprehensive updated list can be found on the Hereditary Hearing Loss Homepage, hereditaryhearingloss.org ). For AR SNHL, the most frequent causative genes in order of frequency are GJB2, SLC26A4, MYO15A, OTOF, CDH23, and TMC1. Common mutations of AD inheritance include WFS1, TECTA, COCH, and KNCQ4. Several of these genes are also implicated in syndromic hearing loss.



Table 1

Nonsyndromic SNHL genes















































































































































































































































AR genes AR genes
DFNB1A GJB2 DFNB88 ELMOD3
DFNB1B GJB6 DFNB89 KARS
DFNB2 MYO7A DFNB91 SERPINB6
DFNB3 MYO15A DFNB93 CABP2
DFNB4 SLC26A4 DFNB98 TSPEAR
DFNB6 TMIE DFNB99 TMEM132E
DFNB7/11 TMC1 DFNB101 GRXCR2
DFNB8/10 TMPRSS3 DFNB102 EPS8
DFNB9 OTOF DFNB103 CLIC5
DFNB12 CDH23
DFNB15/72/95 GIPC3 AD genes
DFNB16 STRC DFNA1 DIAPH1
DFNB18 USH1C DFNA2A KCNQ4
DFNB21 TECTA DFNA2B GJB3
DFNB22 OTOA DFNA3A GJB2
DFNB23 PCDH15 DFNA3B GJB6
DFNB24 RDX DFNA4 MYH14, CEACAM16
DFNB25 GRXCR1 DFNA5 DFNA5
DFNB28 TRIOBP DFNA6/14/38 WFS1
DFNB29 CLDN14 DFNA8/12 TECTA
DFNB30 MYO3A DFNA9 COCH
DFNB31 WHRN DFNA10 EYA4
DFNB32 GPSM2 DFNA11 MYO7A
DFNB35 ESRRB DFNA13 COL11A2
DFNB36 ESPN DFNA15 POU4F3
DFNB37 MYO6 DFNA17 MYH9
DFNB39 HGF DFNA20/26 ACTG1
DFNB42 ILDR1 DFNA22 MYO6
DFNB44 ADCY1 DFNA23 SIX1
DFNB48 CIB2 DFNA25 SLC17A8
DFNB49 MARVELD2 DFNA28 GRHL2
DFNB49 BDP1 DFNA36 TMC1
DFNB53 COL11A2 DFNA41 P2RX2
DFNB59 PJVK DFNA44 CCDC50
DFNB61 SLC26A5 DFNA48 MYO1A
DFNB63 LRTOMT (COMT2) DFNA50 MIRN96
DFNB66/67 LHFPL5 DFNA51 TJP2
DFNB70 PNPT1 DFNA56 TNC
DFNB73 BSND DFNA64 SMAC (DIABLO)
DFNB74 MSRB3 DFNA65 TBC1D24
DFNB76 SYNE4 DFNA67 OSBPL2
DFNB77 LOXHD1
DFNB79 TPRN X-linked genes
DFNB82 GPSM2 DFNX1 (DFN2) PRPS1
DFNB84 PTPRQ DFNX2 (DFN3) POU3F4
DFNB84 OTOGL DFNX4 (DFN6) SMPX
DFNB86 TBC1D24




Autosomal-recessive genes


In AR inheritance, there is often no family history of hearing loss. Although AR SNHL is more common in families in which parents are related (consanguinity), they are not exclusive to such families, and most affected individuals have a negative history of consanguinity within the family tree. According to the hereditary hearing loss homepage, 60 genetic mutations have been identified causing nonsyndromic AR hearing loss.


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 ( 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.



Table 2

Common truncating and nontruncating GJB2 mutations








































































































































































Description Effect
Truncating mutations
35delG del of G at 30–35 Frameshift
235delC del of C at 233–235 Frameshift
W24X G to A at 71 Trp at 24 into Stop
E47X G to T at 139 Glu at 47 into Stop
299–300delAT del of AT at 299 Frameshift
167delT del of T at 167 Frameshift
176–191del16 del of 16 nt at 176 Frameshift
Q57X C to T at 169 Gln at 57 into Stop
269insT ins of T at 269 Frameshift
290–291insA Frameshift Frameshift
Y136X C to A at 408 Tyr at 136 into Stop
30delG del of G at 30–35 Frameshift
312del14 del of 14 nt at 312 Frameshift
M1V (p.0) A to G at 1 No protein production
IVS1 + 1 G to A G to A at −3172 Splice site
333–334delAA del of AA at 333–335 Frameshift
E147X G to T at 439 Glu at 147 into Stop
631delGT del of GT at 631–632 Frameshift
645–648delTAGA del of TAGA at 645 Frameshift
W77X G to A at 231 Trp at 77 into Stop
W44X G to A at 132 Trp at 44 into Stop
Nontruncating mutations
V37I G to A at 109 Val at 37 into Ile
R143W C to T at 427 Arg at 143 into Trp
V27I + E114G G to A at 79 + A to G at 341 Val at 27 into Ile and Glu at 114 into Gly
R127H G to A at 380 Arg at 127 into His
S139N G to A at 416 Ser at 139 into Gln
G12V G to T at 35 Gly at 12 into Val
G45E G to A at 134 Gly at 45 into Glu
H100Y C to T at 298 His at 100 into Tyr
L90P T to C at 269 Leu at 90 into Pro
R32L G to T at 95 Arg at 32 into Leu
V84L G to C at 250 Val at 84 into Leu
K15T A to C at 44 Lys at 15 into Thr
V95M G to A at 283 Val at 95 into Met
K122I A to T at 365 Lys at 122 into Ile
N206S A to G at 617 Gln at 206 into Ser
delE120 del of GAG at 360 del of Glu at 119–120
R32C C to T at 94 Arg at 32 into Cis
R184P G to C at 551 Arg at 184 into Pro


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.

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Mar 28, 2017 | Posted by in OTOLARYNGOLOGY | Comments Off on Genetics of Hearing Loss—Nonsyndromic
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