Non-syndromic hearing loss

Non-syndromic hearing loss can be partial or total and is not associated with other signs or symptoms. It accounts for approximately 70% of all cases of genetic hearing loss. The remaining 30% of hearing loss cases with a genetic cause present with additional clinical features as part of a wider syndromic diagnosis; this is termed syndromic hearing loss.

Over 120 genes have been identified as causing non-syndromic hearing loss, and the condition can be inherited in either an autosomal recessive or autosomal dominant pattern.

Non-syndromic hearing loss can be unilateral or bilateral and has a spectrum of severity from mild to profound. The pattern of hearing loss can also vary – for example, impairment can be more pronounced at particular sound frequencies. The condition can be classified in several ways, including those listed below.

• Mode of inheritance:
  • autosomal dominant (about 20% of cases);
  • autosomal recessive (most common, about 80%–85% of cases);
  • X-linked; or
  • mitochondrial.
• Time of onset:
  • prelingual (before speech development); or
  • postlingual.
• Pathogenesis:
  • sensorineural (most common), including:
    • sensory: disruption of transformation of sound within the cochlea; and
    • neural: disruption of sound transmission beyond the cochlea along the neural pathway;
  • conductive (less common): disruption of conduction of sound to the cochlea; or
  • mixed (less common): a combination of sensorineural and conductive.
• Natural history:
  • progressive; or
  • non-progressive.

Diagnosis may follow newborn screening (which detects moderate to profound hearing loss but may miss mild hearing loss), routine screening within the school setting or evaluation in childhood following parental concern and/or delayed speech and language development.

• There are over 120 genes identified to cause non-syndromic hearing loss.
• There are two important genomic testing points to remember:
  • different variants in the same gene can cause different forms of hearing loss – for example, GJB6 can be implicated in both autosomal dominant and autosomal recessive hearing loss; and
  • some genes are implicated in both non-syndromic and syndromic hearing loss – for example, CDH23 is implicated in autosomal recessive hearing loss and Usher syndrome type 1D.

The most frequently observed genes and their associated features are shown in table 1 below.

Table 1: The genes most commonly identified as causing non-syndromic hearing loss

*Variants in GJB2 and GJB6 are also implicated in autosomal dominant hearing loss.

**A bedside test is in development that can be used to identify the m.1555A>G variant before aminoglycoside administration, allowing an alternative antibiotic to be chosen in a timely manner if the variant is identified.

For information about genomic testing, see Presentation: Child with non-syndromic hearing loss.

Autosomal recessive non-syndromic hearing loss

The parents of most affected individuals are carriers and are therefore likely to have a 25% (one-in-four) chance of having another affected child. Parental carrier testing should be offered, where relevant, to confirm that parents are carriers and that the variants are present on both copies of the gene (in trans) rather than on the same copy inherited from one parent (in cis).

Autosomal dominant non-syndromic hearing loss

Affected individuals have a 50% chance of passing the condition on to each of their children. Parents and wider family members may be offered targeted testing for the pathogenic variant to determine their carrier status, as several genes demonstrate incomplete penetrance and variable expressivity.

X-linked recessive non-syndromic hearing loss

Males who carry a pathogenic variant for an X-linked recessive condition will be affected. Where the father has the condition:

• each daughter will be a carrier, as they always inherit their father’s X chromosome; and
• sons cannot inherit an X-linked recessive condition, as they always inherit their father’s Y-chromosome.

Females rarely show signs of X-linked recessive conditions because they usually have a second standard copy of the gene on their other X chromosome. They are instead referred to as a carrier (though female carriers of a POU3F4 variant may have mild hearing loss). Where the mother is a carrier for the condition:

• each daughter will have a 50% chance of being a carrier for the same condition; and
• each son has a 50% chance of inheriting the pathogenic variant and having the condition.

Mitochondrial non-syndromic hearing loss

Conditions that are the result of pathogenic variants in mitochondrial DNA (mtDNA) are passed on through the maternal line, as mitochondrial DNA in humans is derived exclusively from the egg cell. The transmission of mitochondrial conditions is complicated by heteroplasmy (the presence of more than one mtDNA within a cell). This can be an important factor in determining penetrance and severity of mitochondrial conditions.

Management of children with non-syndromic hearing loss is complex and should be delivered via a multidisciplinary team. In addition to genomic testing, children require a comprehensive non-genetic work-up, including:

• toxoplasma, rubella, cytomegalovirus and herpes (TORCH) screening, which investigates congenital infection;
• audiological assessment; and
• cranial imaging, which can reveal pathognomonic features.

Cochlear implantation is considered for many children with severe to profound hearing loss.

For clinicians

• GeneReviews: Genetic hearing loss overview
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• Nature Education: mtDNA and mitochondrial diseases
• NHS England: National Genomic Test Directory
• StatPearls: Hearing loss
• US National Library of Medicine: ClinicalTrials.gov database

References:

• Del Castillo I, Morín M, Domínguez-Ruiz M and others. ‘Genetic etiology of non-syndromic hearing loss in Europe’. Human Genetics 2022: volume 141, pages 683–696. DOI: 10.1007/s00439-021-02425-6
• Firth HV and Hurst JA. ‘Oxford Desk Reference: Clinical Genetics and Genomics, second edition’. Oxford University Press 2017: pages 122–125. DOI: 10.1093/med/9780199557509.001.0001

For patients

• Royal National Institute for Deaf People
• National Deaf Children’s Society