Genetic Testing for Young Adults with Nonsyndromic Sensorineural Hearing Loss
First-Line Genetic Test
For a young adult with sensorineural hearing loss, no other symptoms, and no family history, order GJB2 (connexin 26) gene sequencing as the initial genetic test. 1, 2
- GJB2 mutations account for the largest proportion of autosomal recessive nonsyndromic hearing loss in the United States and many populations. 1, 2
- A positive GJB2 result can avoid expensive and potentially invasive additional testing. 1
- The absence of family history does NOT exclude genetic causes—autosomal recessive inheritance commonly presents as simplex cases with a 25% recurrence risk in future offspring. 1, 2
Critical Pre-Test Evaluation Required
Before ordering genetic testing, you must exclude environmental causes:
- CMV testing: Obtain CMV antibody testing to exclude congenital CMV-related hearing loss (though a positive result requires cautious interpretation). 1
- Ototoxic drug exposure: Document any history of aminoglycoside exposure or other ototoxic medications. 1
- Acoustic trauma, meningitis, ECMO exposure, or hypoxia: Rule out these acquired causes through targeted history. 1, 2
Perform a thorough physical examination to identify occult syndromic features:
- Cardiac evaluation (syncope, arrhythmia, prolonged QT interval, congenital heart defects). 1
- Renal assessment (hematuria, proteinuria, structural defects). 1
- Integumentary changes (premature graying, white forelock, abnormal pigmentation, keratoderma). 1
- Dysmorphology (preauricular pits, branchial cysts, cleft palate, dental anomalies). 1
- Ophthalmologic abnormalities and thyroid examination. 1
If GJB2 Testing is Negative
Order a comprehensive hearing loss gene panel using next-generation sequencing (NGS) that covers all genes associated with nonsyndromic and common syndromic hearing loss. 1, 2
- Comprehensive HL NGS panels have a diagnostic yield of approximately 40% for nonsyndromic hearing loss. 1, 3
- Panels typically include 100-300 genes, with an average of 121 genes per panel. 1
- Ensure the panel includes copy number variant (CNV) analysis, as deletions/duplications (particularly in STRC gene) are common causes that may be missed by sequence-only analysis. 1
Additional Testing Considerations
If mitochondrial inheritance is suspected based on maternal transmission pattern:
- Test for A1555G mutation (associated with aminoglycoside-induced hearing loss) and A7445G mutation after excluding common GJB2 mutations. 1
If comprehensive gene panel is negative and syndromic features are present:
- Consider exome sequencing (ES) or genome sequencing (GS), which have diagnostic yields of 30-35% for ES. 1
Common Pitfalls to Avoid
- Do not assume isolated hearing loss is nonsyndromic without thorough examination: Approximately 30% of genetic hearing loss is syndromic, and 20% of genetically diagnosed "nonsyndromic" cases reveal unrecognized syndromes. 2
- A negative GJB2 test does NOT exclude genetic etiology: The test only evaluates one gene among hundreds that can cause hearing loss. 1, 2
- Absence of family history is NOT reassuring: Most genetic hearing loss is autosomal recessive and presents without family history. 1, 2
- Verify panel performance characteristics: Ensure adequate coverage of all regions of interest, as some panels analyze only a subset of exome data with potential gaps in coverage. 1
Clinical Utility of Genetic Diagnosis
Identifying the genetic cause provides:
- Accurate genetic counseling with precise recurrence risk estimation. 2
- Prognostic information about progression and severity. 2, 3
- Detection of associated systemic manifestations requiring surveillance (e.g., cardiac, renal, ophthalmologic). 2, 3
- Prevention strategies, such as avoiding aminoglycosides in patients with mitochondrial mutations. 2
- Determination of candidacy for specific therapies and interventions. 2