Genetic Testing for Young Adults with Sensorineural Hearing Loss
First-Line Testing
Start with GJB2 (connexin 26) gene sequencing as the initial genetic test, as GJB2 mutations account for the majority of autosomal recessive nonsyndromic hearing loss and represent the single most important genetic cause of childhood deafness. 1, 2, 3
- GJB2 testing should be performed first in young adults presenting with isolated sensorineural hearing loss, no other symptoms, and no family history 1, 2
- This approach is cost-effective and can avoid expensive additional testing if positive 1
- The absence of family history does NOT exclude genetic causes, as autosomal recessive inheritance commonly presents without family history and carries a 25% recurrence risk in future offspring 1
If GJB2 Testing is Negative
Proceed to a comprehensive hearing loss gene panel (typically 60-230 genes) that includes copy number variant (CNV) analysis, as the diagnostic yield for hereditary hearing loss is approximately 20-40% with next-generation sequencing panels. 2, 4, 5
- Modern panels should include 60-230 genes covering both syndromic and nonsyndromic hearing loss 4, 6, 7
- Ensure the panel includes CNV analysis, as deletions/duplications (particularly in STRC gene) are common but technically challenging to detect 2
- Whole-genome sequencing (WGS) is increasingly preferred over whole-exome sequencing as it can identify cryptic splice variants, mitochondrial variants, structural variants, and transposable element insertions that WES misses 5
Critical Pre-Test Evaluation
Before ordering genetic testing, exclude environmental causes through targeted history:
- CMV testing to rule out congenital CMV infection 1, 2
- Document exposure to ototoxic drugs (particularly aminoglycosides) 1
- Rule out acoustic trauma, meningitis, ECMO exposure, and hypoxia 1
Perform thorough physical examination to identify occult syndromic features:
- Visual abnormalities (ophthalmology evaluation) 1, 8
- Cardiac evaluation (EKG to rule out long QT syndrome) 1, 8
- Renal assessment (renal function studies) 1, 8
- Pigmentary changes (Waardenburg syndrome features) 1
- Facial/cervical features 1
- Thyroid function studies 8
- CT scan of temporal bones to identify enlarged vestibular aqueducts or Mondini malformations, found in 18% of patients with sensorineural hearing loss 8
Common Pitfalls to Avoid
- Do NOT assume isolated hearing loss is nonsyndromic without thorough examination, as approximately 30% of genetic hearing loss is syndromic, and 20% of genetically diagnosed "nonsyndromic" cases reveal unrecognized syndromes 1
- A negative GJB2 test does NOT exclude genetic etiology—many patients still have underlying genetic causes 1, 2, 3
- A negative comprehensive genetic panel does NOT mean the hearing loss is not genetic, as approximately 30% of patients will have no obvious etiology on initial evaluation but many still have an underlying genetic cause 2
Panel Selection Technical Considerations
- Verify that the panel has adequate coverage of all regions of interest, as some panels analyze only a subset of exome data with potential gaps in coverage 2
- Laboratories specializing in hearing loss genetics may have superior approaches for analyzing difficult genomic regions 2
- Ensure the panel includes analysis of mitochondrial genes (MT-RNR1, MT-CO1) and common structural variants 6, 5
Clinical Utility of Genetic Diagnosis
Identifying the genetic cause provides:
- Accurate genetic counseling and recurrence risk assessment 1, 4
- Prognostic information about progression and severity 1, 4
- Detection of associated systemic manifestations requiring surveillance 1, 4
- Prevention strategies, such as avoiding aminoglycosides in patients with mitochondrial mutations 1
- Identification of unrecognized syndromes (e.g., Stickler syndrome, PHARC syndrome) that require specific management 4