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Hereditary hearing loss accounts for most newborn hearing loss identified in the United States, and significant hearing loss occurs in as many as 3 in 1,000 children. Although it is unclear what proportion of adult-onset hearing loss is due to genetics, hearing loss is estimated to develop in roughly half of all individuals by late life. Syndromic hearing loss (ie, hearing loss occurring alongside abnormalities within other organ systems) is less common than nonsyndromic hearing loss, which accounts for a majority of hereditary cases.
Depending on the clinical factors associated with hearing loss (eg, age of onset, type, symmetry, laterality, severity, stability, organ system involvement, medical history, family history, etc.), a specific etiology may be suspected, and targeted genetic testing can be used to confirm a diagnosis. In cases without an apparent etiology or informative clinical features, broad genetic testing is appropriate.
Quick Answers for Clinicians
The American Academy of Pediatrics (AAP) recommends universal screening for hearing loss in all newborns and provides additional recommendations for infants with specific risk factors (eg, congenital cytomegalovirus infection, family history of childhood hearing loss, etc.). Because delayed-onset hearing loss is possible, the AAP further recommends an age-based schedule for screening in all children through adolescence. Regardless of age, a prompt, objective hearing screen is recommended when clinical or caregiver concern arises due to changes in hearing. A clinical genetics evaluation, including genetic counseling, should be offered to every child with confirmed hearing loss.
Unilateral hearing loss can have a range of etiologies (eg, infection, injury, autoimmune disease, genetic variation, etc.). Although the diagnostic yield of multigene panel testing is low (5% or less) in patients with unilateral hearing loss, genetic testing should be considered if nonhereditary causes are ruled out or if a hereditary cause appears possible. In such circumstances, multigene panel testing by next generation sequencing is suggested.
Traditionally, environmental factors such as sound exposure have been the primary etiologic focus in late-onset hearing loss. Nevertheless, genetics are known to play a role, with recent studies identifying a causative variant in up to a third of cases. As with childhood hearing loss, the evaluation of hearing loss in adult patients is largely guided by clinical factors. Thus, genetic testing may be appropriate to investigate late-onset hearing loss.
Indications for Testing
Genetic testing is indicated in individuals who have confirmed hearing loss and a clinical picture compatible with a hereditary cause.
Laboratory Testing
The American College of Medical Genetics and Genomics (ACMG) recommends different approaches to testing depending on the age of onset and the presence (or absence) of informative clinical features and findings. All genetic testing should be preceded and followed by genetic counseling. When broad panel testing is performed, the ACMG recommends the use of a panel that includes genes determined to be relevant by the Hearing Loss Gene Curation Expert Panel. ,
Before testing, a thorough clinical evaluation should be conducted to identify relevant facts and features. In infants, children, and young adults, evaluation includes medical, birth, and family histories and a physical examination. In adults with hearing loss, evaluation should be informed by the age of onset and hearing loss characteristics.
Syndromic Hearing Loss
In patients with findings suggestive of a specific syndromic etiology (eg, Pendred syndrome, Usher syndrome, etc.), targeted testing is appropriate to confirm a diagnosis. Test selection should be informed by previous findings but may include single- or multigene sequencing, chromosomal analysis, or copy number analysis by microarray or next generation sequencing. Exome and genome sequencing may also be considered, although these methods may introduce difficulties in interpretation (eg, filtering a large number of identified variants, causally linking variants to candidate genes, or incidentally identifying a genetic susceptibility unrelated to hearing loss) or detection of specific variant types (eg, technically challenging regions to analyze by next generation sequencing or regions not included in the exome capture).
When targeted testing fails to yield a syndromic diagnosis, or when the syndrome diagnosed does not commonly result in hearing loss, expansive multigene panel testing should be performed, followed by exome or genome sequencing if panel results do not reveal an etiology.
Nonsyndromic Hearing Loss
In the absence of findings and features suggestive of a specific genetic syndrome, a more comprehensive approach to testing is recommended to determine an etiology. An expansive multigene panel should be used initially, with exome or genome sequencing to follow if panel testing is negative. Importantly, new variant-disease associations are continually being identified, and a negative result does not rule out a genetic cause.
Because some forms of syndromic hearing loss can be mistaken for nonsyndromic hearing loss, children and adolescents with hearing loss of uncertain etiology despite recommended testing should be referred to a clinical geneticist for further evaluation.
Follow-Up and Variant Reclassification
The Association for Molecular Pathology (AMP) and the ACMG jointly recommend that genetic testing be used in conjunction with other clinical evidence whenever possible to issue a diagnosis. In the presence of supportive clinical findings, variants classified as “likely pathogenic” or “pathogenic” are sufficient to guide clinical management. However, in patients with “likely pathogenic” variants, follow-up testing (eg, testing relatives to confirm inheritance, segregation with disease in the family, or variant phase) is recommended to support any future reclassification of a variant as “pathogenic.”
In patients in whom an etiology cannot be determined, the ACMG suggests follow-up with a geneticist every 3 years, as new testing and updated variant classifications may become available. Follow-up testing may also yield additional information in individuals with subtly progressive symptoms.
ARUP Laboratory Tests
Massively Parallel Sequencing
Polymerase Chain Reaction (PCR)/Capillary Electrophoresis
References
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Li MM, Tayoun AA, DiStefano M, et al. Clinical evaluation and etiologic diagnosis of hearing loss: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2022;24(7):1392-1406.
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Bower C, Reilly BK, Richerson J, et al. Hearing assessment in infants, children, and adolescents: recommendations beyond neonatal screening. Pediatrics. 2023;152(3):e2023063288.
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AAP - Recommendations-preventive pediatric health care
Bright Futures, American Academy of Pediatrics. Recommendations for preventive pediatric health care. American Academy of Pediatrics. Updated Jun 2024; accessed Oct 2024.
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Hearing loss gene curation expert panel
Clinical Genome Resource. Hearing loss gene curation expert panel. Accessed Oct 2024.
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Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.