Genotype–Phenotype Relationship in Inherited Disorders of Hearing Impairment


Hearing impairment is a genetically heterogeneous disorder. Many causative genes have been described, and the number is still expanding. Nonsyndromic hearing impairment has several clinical characteristics that may point into the direction of a certain gene, but this is not often the case. Syndromic hearing impairment is characterised by additional clinical symptoms, which may direct diagnostics towards the analysis of specific genes. However, the distinction between nonsyndromic hearing impairment and the syndromic forms of the disorder is becoming blurred when looking at the causative genes. The spectrum of mutations from mild to severe in one gene can lead to completely different clinical symptoms, and the phenotype–genotype relation is ever expanding. The molecular diagnosis of hearing impairment is challenging but has benefited tremendously from the introduction of massive parallel sequencing techniques.

Key Concepts

  • Hearing impairment can be syndromic or nonsyndromic, but extensive overlap exists in the genes involved.
  • Specific clinical characteristics of nonsyndromic hearing impairment have limited value in determining which gene is involved.
  • Syndromic hearing impairment is caused by a plethora of genes, and severe versus mild mutations in the same gene can lead to very different phenotypes.
  • Molecular diagnosis of hearing impairment is preferably done using massive parallel sequencing techniques.
  • In the coming years more genes will be discovered to be involved in hearing impairment.

Keywords: characteristics of hearing impairment; audiogram; DFNB; DFNA; DFNX; Usher syndrome; Heimler syndrome; massive parallel sequencing; exome sequencing

Figure 1. Examples of typical audiograms found in sensorineural hearing impairment: only AC thresholds are shown, BC thresholds were consistent without airbone gaps. (a) TMPRSS3 with a ‘ski‐slope’ configuration; (b) TECTA with a ‘cookie‐bite’ configuration and (c) WFS1 with low‐frequency HL.


Ben Said M, Grati M, Ishimoto T, et al. (2016) A mutation in SLC22A4 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non‐syndromic hearing loss DFNB60. Human Genetics 135: 513–524.

del Castillo FJ, Rodriguez‐Ballesteros M, Alvarez A, et al. (2005) A novel deletion involving the connexin‐30 gene, del(GJB6‐d13s1854), found in trans with mutations in the GJB2 gene (connexin‐26) in subjects with DFNB1 non‐syndromic hearing impairment. Journal of Medical Genetics 42: 588–594.

Dahmani M, Ammar‐Khodja F, Bonnet C, et al. (2015) EPS8L2 is a new causal gene for childhood onset autosomal recessive progressive hearing loss. Orphanet Journal of Rare Diseases 10: 96.

Fortnum HM, Summerfield AQ, Marshall DH, Davis AC and Bamford JM (2001) Prevalence of permanent childhood hearing impairment in the United Kingdom and implications for universal neonatal hearing screening: questionnaire based ascertainment study. BMJ 323: 536–540.

Hoefsloot LH, Roux AF and Bitner‐Glindzicz M (2013) EMQN Best Practice guidelines for diagnostic testing of mutations causing non‐syndromic hearing impairment at the DFNB1 locus. European Journal of Human Genetics 21 (11): 1325–1329.

Hoefsloot LH, Feenstra I, Kunst HP and Kremer H (2014) Genotype phenotype correlations for hearing impairment: approaches to management. Clinical Genetics 85: 514–523.

Li J, Zhao X, Xin Q, et al. (2015) Whole‐exome sequencing identifies a variant in TMEM132E causing autosomal‐recessive nonsyndromic hearing loss DFNB99. Human Mutation 36: 98–105.

Patton J, Brewer C, Chien W, et al. (2016) A genotypic ascertainment approach to refute the association of MYO1A variants with non‐syndromic deafness. European Journal of Human Genetics 25: 147–149.

Pique LM, Brennan ML, Davidson CJ, et al. (2014) Mutation analysis of the SLC26A4, FOXI1 and KCNJ10 genes in individuals with congenital hearing loss. PeerJ 2: e384.

Rodriguez‐Paris J and Schrijver I (2009) The digenic hypothesis unraveled: the GJB6 del(GJB6‐D13S1830) mutation causes allele‐specific loss of GJB2 expression in cis. Biochemical and Biophysical Research Communications 389: 354–359.

Simon M, Richard EM, Wang X, et al. (2015) Mutations of human NARS2, encoding the mitochondrial asparaginyl‐tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome. PLoS Genetics 11: e1005097.

Snoeckx RL, Huygen PL, Feldmann D, et al. (2005) GJB2 mutations and degree of hearing loss: a multicenter study. American Journal of Human Genetics 77: 945–957.

Tekin D, Yan D, Bademci G, et al. (2016) A next‐generation sequencing gene panel (MiamiOtoGenes) for comprehensive analysis of deafness genes. Hearing Research 333: 179–184.

Zazo Seco C, Serrao de Castro L, van Nierop JW, et al. (2015) Allelic mutations of KITLG, encoding KIT ligand, cause asymmetric and unilateral hearing loss and Waardenburg Syndrome Type 2. American Journal of Human Genetics 97: 647–660.

Zazo Seco C, Wesdorp M, Feenstra I, et al. (2017) The diagnostic yield of whole‐exome sequencing targeting a gene panel for hearing impairment in The Netherlands. European Journal of Human Genetics 25: 308–314.

Further Reading

Sloan‐Heggen CM, Bierer AO, Shearer AE, et al. (2016) Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Human Genetics 135: 441–450.

Smith RJH, Shearer AE, Hildebrand MS, et al. (1999) Deafness and Hereditary Hearing Loss Overview [Updated 2014 Jan 9]. In: Pagon RA, Adam MP, Ardinger HH, et al. (eds) GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993‐2017. Available from:

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How to Cite close
Hoefsloot, Lies H, and Roux, Anne‐Francoise(Jul 2017) Genotype–Phenotype Relationship in Inherited Disorders of Hearing Impairment. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026842]