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Genetics of Hearing Impairment

Genetic forms of hearing loss and deafness can be syndromic (associated with malformation of the external ear or other external organs with medical problems involving other organ systems), or non-syndromic (no associated visible abnormalities of the external ear or related medical problems). Among the genetic forms, approximately 30% are syndromic, while 70% are non-syndromic. So far, more than 400 genes have been identified which are responsible for hearing impairment.

Syndromic Hearing Impairment

Patterns of Inheritance

Hearing deficits can be inherited in one of the four ways:

    • 1. Autosomal dominant
    • 2. Autosomal recessive
    • 3. X-link
    • 4. Mitochondrial patterns of inheritance
  • In an autosomal dominant pattern of inheritance (Fig.1), a child inherits a normal copy of a gene from one parent and an abnormal gene from the other parent. The abnormal gene dominates the normal gene, so one copy of an abnormal gene is sufficient to cause an autosomal dominant disorder. Waardenburg syndrome is the most common cause of autosomal dominant syndromic hearing loss, affecting 1 in 42,000 people. Other hearing impairments inherited in this fashion include Branchiootorenal syndrome, Stickler syndrome and Neurofibromatosis 2.

    Autosomal Recessive: In this pattern of inheritance, two copies of the abnormal gene are required to cause the disorder (Fig-2). Individuals who inherit only one abnormal gene and one normal gene are referred to as carriers and are not affected by the disorder. Individuals affected by an autosomal recessive disorder usually are the result of mating between two carriers. Consanguinity increases the risk of an autosomal recessive disorder.Each child of two carrier parents has a 25% chance of inheriting two abnormal copies and thus having hearing loss. However, autosomal recessive disorders are typically not seen in every generation of an affected family because an abnormal copy of the gene may be passed on from one (unaffected) carrier to the next for many generations before a couple, who by chance both carry an abnormal copy, has an affected child. Usher syndrome is the most common type of autosomal recessive syndromic hearing loss. Others include Pendred syndrome and Jervell & Lange-Nielsen syndrome.

    X-linked hearing defects are inherited through genes on the X chromosome (Fig.3). Males only carry one X chromosome. Therefore, they are more susceptible to an X-linked disorder. In X-linked disorders, affected fathers usually pass on the abnormal gene to their daughters, but not to their sons. More than 80% of Alport syndrome patients have an X-linked disorder associated with sensorineural hearing loss.

    Mitochondrial patterns of inheritance: Mitochondrial disorders are inherited exclusively through the maternal line. Children inherit all of the mtDNA from mothers, so if the hearing loss is caused by a mutation in mtDNA, all the children of affected mothers (but none of the children of affected fathers) would be expected to have hearing loss. A mtDNA mutation, in which a G instead of an A is found at position 1555 (called A1555G), causes severe to profound sensorineural hearing loss.

    Candidate Genes for Syndromic Hearing Impairment

    Autosomal dominant syndromic hearing impairment
    Disorder Subtype Gene
    Waardenburg syndrome WS I PAX3
      WS II MITF
      WS III PAX3
      WS IV EDNRB,EDN3,SOX10
    Branchiootorenal syndrome   EYA 1, SIX1,SIX5
    Stickeler Syndrome STL1 COL2A1
      STL2 COL11A1
      STL3 COL11A2
    Neurofibromastosis2   NF2

    Autosomal recessive syndromic hearing impairment
    Disorder Subtype Gene
    Usher syndrome Type I CDH23,MYO7A,PCDH15,USH1C,USH1G
      Type II USH2A,GPR98
      Type III CLRN1
    Pendred syndrome   SLC26A4
    Jervell and Lange-Nielsensyndrome   KCNE1,KCNQ1
    Refsum disease   PHYH,PEX7

    X-linked syndromic hearing impairment
    Disorder Subtype Gene
    Alport syndrome   COL4A3,COL4A4,COL4A5
    Mohr-Tranebjaerg syndrome   TIMM8A

    Mitochondrial syndromic hearing impairment
    Disorder Subtype Gene
    Kearns-Sayre syndrome   MELAS,MERRF,NARP

    Non-Syndromic Hearing Impairment

    More than 70% of hereditary hearing loss is non-syndromic. The different gene loci for nonsyndromic deafness are designated DFN. Loci are named based on mode of inheritance.

    • DFNA: Autosomal dominant
    • DFNB: Autosomal recessive
    • DFNX:X-linked
  • Most autosomal dominant loci cause post-lingual hearing impairment. There is no identifiable single gene responsible for majority of cases (Table-1).

    Table 1- Known genes causing autosomal dominant non-syndromic hearing impairment
    Locus Name Gene Onset/Decade Audio profile
    DFNA1 DIAPH1 Postlingual/1st Low frequency progressive
    DFNA2 KCNQ4 Postlingual/2nd High frequency progressive
    DFNA2B GJB3 Post lingual/4th High frequency progressive
    DFNA3 GJB2, GBJ6 Prelingual High frequency progressive
    DFNA4 MYH14 Postlingual Flat/gently downsloping
    DFNA5 DFNA5 Postilngual/1st High frequency progressive
    DFNA6/14/38 WFSI Prelingual Low frequency progressive
    DFNA8/12 TECTA Prelingual Mid-frequency loss
    DFNA9 COCH Postlingual/2nd High frequency progressive
    DFNA10 EYA4 Post lingual/3rd,4th Flat/gently down sloping
    DFNA11 MYO7A Post lingual/1st Flat/gently down sloping
    DFNA13 COL11A2 Postlingual/2nd Mid-frequency loss
    DFNA15 POU4F3 Post lingual High frequency progressive
    DFNA17 MYH9 Post lingual High frequency progressive
    DFNA20/26 ACTG1 Post lingual High frequency progressive
    DFNA22 MYO6 Post lingual High frequency progressive
    DFNA23 SIX1 Prelingual Down sloping
    DFNA25 SLC17A8 Postlingual/2nd-6th decades High frequency progressive
    DFNA28 GRHL2 Postlingual Flat/Gently downsloping
    DFNA36 TMC1 Postlingual Flat/Gently downsloping
    DFNA39 DSPP Postlingual High frequency progressive
    DFNA41 P2RX2 Postlingual Flat progressive
    DFNA44 CCD50 Postlingual Low to mild frequencies progressive
    DFNA48 MYO1A Postlingual Progressive
    DFNA50 MIR96 Postlingual/2nd Flat progressive
    DFNA51 TJP2 & FAM189A2 Postlingual/4th High frequency progressive
    Adapted from Van Camp & Smith [2010]

    Most autosomal recessive loci cause prelingual severe-to-profound hearing loss. An exception is DFNB8, in which the hearing impairment is prelingual and rapidly progressive. About 50% of autosomal recessive nonsyndromic hearing loss has been attributed to mutations in the gene GJB2. The remaining 50% have mutations in numerous other genes (Table-2).

    Table 2- Known genes causing autosomal recessive non-syndromic hearing impairment
    Locus Name Gene Onset Type
    DFNB1 GJB2, GJB6 Prelingual Usually stable
    DFNB2 MYO7A Prelingual, Postlingual Unspecified
    DFNB3 MYO15A Prelingual Severe to profound; stable
    DFNB6 TMIE Prelingual Severe to profound; stable
    DFFNB9N7/11 TMC1 Prelingual Severe to profound; stable
    DFNB8/10 TMPRSS3 Postlingual, Prelingual Progressive, stable
    DFNB9 OTOF Prelingual Usually severe to profound;stable
    DFNB12 CDH23 Prelingual Severe to profound; stable
    DFNB16 STRC Prelingual Severe to profound; stable
    DFNB18 USH1C Prelingual Severe to profound; stable
    DFNB21 TECTA Prelingual Severe to profound; stable
    DFNB22 OTOA Prelingual Severe to profound; stable
    DFNB23 PCDH15 Prelingual Severe to profound; stable
    DFNB24 RDX Prelingual Severe to profound; stable
    DFNB25 GRXCR1 Prelingual Moderate to profound ; progressive
    DFNB28 TRIOBP Prelingual Severe to profound; stable
    DFNB29 CLDN14 Prelingual Severe to profound; stable
    DFNB30 MYO3A Prelingual Severe to profound; stable
    DFNB31 CHRN Prelingual -
    DFNB32/82 GPSM2 Prelingual Severe to profound; stable
    DFNB35 ESRRB Unknown Severe to profound
    DFNB36 ESPN Prelingual -
    DFNB37 MYO6 Prelingual -
    DFNB39 HGF Prelingual Severe to profound; down sloping
    DFNB49 MARVELD2 Prelingual Moderate to profound; stable
    DFNB53 COL11A2 Prelingual Severe to profound; stable
    DFNB59 DFNB59 Prelingual Severe to profound; stable
    DFNB61 SLC26A5 Prelingual Severe to profound; stable
    DFNB63 LRTOMT Prelingual Severe to profound; stable
    DFNB67 LHFPL5 Prelingual Severe to profound; stable
    DFNB73 BSND Prelingual Severe to profound; stable
    DFNB76 SYNE4 Prelingual High frequency; progressive
    DFNB77 LOXHD1 Postlingual Moderate to profound; progressive
    DFNB79 TPRN Prelingual Severe to profound; stable
    DFNB84 PTPRQ Prelingual Moderate to profound; progressive
    Adapted from Van Camp & Smith [2010]

    X-linked nonsyndromic hearing loss can be either pre-or postlingual. Mutations of PRPS1, POU3F4 and SMPX have been identified in X-linked syndromic hearing impairment (Table-3).

    Table 3- X-Linked nonsyndromic hearing impairment causative genes
    Locus Name Gene Onset Type and Degree Frequencies
    DFNX1 (DFN2) PRPS1 Postlingual Progressive sensorineural;severe to profound All
    DFNX2 (DFN3) POU3F4 Prelingual Progressive,mixed;variable,but progresses to profound All
    DFNX4 (DFN6) SMPX Postlingual Progressive sensorinueral;mild to profound All
    Adapted from Van Camp & Smith [2010]

    Mutations in the mitochondrial genes MT-RNR1, MT-TS1, and/or MT-CO1 have been reported to cause non-syndromic hearing loss (Table-4).

    Table 4- Mitochondrail genes responsible for non-syndromic hearing impairment
    Gene Mutation Severity Penetrance
    MT-RNRI 961 different mutations, 1494C>T, 1555A>G Variable Highly variable, Aminoglycoside induced
    MT-TSI 7445A>G, 7472insC, 7510T>C, 7511T Variable Highly variable
    MT-CO1 7444G>A Severe to profound Complete, aminoglycoside associated ; associated with MT-RNR1 1555A>G
    Adapted from Van Camp & Smith [2010]

    Molecular Genetic Testing

    Genetic testing for the cause of non-syndromic hearing impairment is available by combining the polymerase chain reaction and DNA sequencing techniques. Sequencing of GJB2 and GJB6 should be considered first, in the evaluation of individuals with congenital non syndromic sensorineural hearing loss. In other cases, the extreme genetic heterogeneity and frequent lack of phenotypic variability make genetic diagnosis difficult using single gene screening technique. Therefore multi-gene screening panels have been developed to screen for the cause of hearing loss by different laboratories and groups. These screening panels vary by laboratory both in the techniques used and number of genes sequenced.

    Important References
    Smith RJH, Shearer AE, Hildebrand MS, Van Camp G. Deafness and Hereditary Hearing Loss Overview. In: Pagon RA et al, editors. Gene Reviews, Seattle (WA): University of Washington, Seattle; 1993-2014. Van Camp G, Smith RJH. The Hereditary Hearing Loss Homepage. Available online. 2010