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
- Ensure the panel includes CNV analysis, particularly for STRC gene deletions/duplications, which are common but technically challenging to detect 2
- Modern panels should cover 196-229 genes related to both syndromic and nonsyndromic hearing loss 4
- Whole-genome sequencing may identify variants missed by standard panels, including cryptic splice variants, mitochondrial variants, structural variants, and transposable element insertions 5
Critical Pre-Test Evaluation
Before ordering genetic testing, exclude environmental causes through targeted history 1:
- CMV testing to rule out congenital CMV infection 1, 2
- Ototoxic drug exposure (particularly aminoglycosides) 1
- Acoustic trauma history 1
- Meningitis, ECMO exposure, or hypoxia 1
Perform a thorough physical examination to identify occult syndromic features 1:
- Visual abnormalities (ophthalmology evaluation) 1
- Cardiac evaluation (EKG to rule out long QT syndrome) 1
- Renal assessment (renal function studies) 1
- Pigmentary changes 1
- Facial/cervical features 1
- Thyroid function 6
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 other genes can cause hearing loss 1, 3
- A negative comprehensive genetic panel does NOT mean the hearing loss is not genetic—approximately 60-80% of patients will have no molecular diagnosis on initial testing, but many still have an underlying genetic cause 2, 4
Clinical Utility of Genetic Diagnosis
Identifying the genetic cause provides 1:
- Accurate genetic counseling and recurrence risk assessment 1
- Prognostic information about progression and severity 1
- Detection of associated systemic manifestations requiring surveillance 1
- 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
Panel Selection Considerations
When choosing a laboratory 2:
- Verify adequate coverage of all regions of interest, as some panels analyze only a subset of exome data with potential gaps 2
- Ensure CNV analysis is included, as deletions/duplications are common causes 2
- Consider laboratories specializing in hearing loss genetics, as they may have superior approaches for analyzing difficult genomic regions 2
Population-Specific Considerations
- The most common pathogenic mutations vary by ethnicity: 35delG is prevalent in Caucasian populations, while other mutations predominate in Asian and other ethnic groups 3
- In Japan, the overall diagnostic rate is 38.8%, with higher rates in congenital/early-onset cases (48.6%) compared to adult-onset cases (18.0%) 7