What is the usual gene panel ordered in a young adult with sensorineural hearing loss, no other symptoms, and no family history of hearing loss?

Genetic Testing for Young Adults with Nonsyndromic Sensorineural Hearing Loss

Initial Genetic Testing Approach

For a young adult with isolated sensorineural hearing loss, no other symptoms, and no family history (simplex case), start with GJB2 (connexin 26) gene sequencing as the first-line genetic test. 1

This targeted approach is recommended because:

• GJB2 mutations account for the majority of autosomal recessive nonsyndromic hearing loss in the United States, making it the highest-yield single gene test 1
• A positive result can avoid expensive and potentially invasive additional testing 1
• The absence of family history does not exclude genetic causes—patients with recessive nonsyndromic hearing loss commonly present as simplex cases with a 25% recurrence risk in future offspring 1

Comprehensive Multi-Gene Panel Testing

If GJB2 testing is negative or if comprehensive evaluation is preferred from the outset, order a next-generation sequencing (NGS) panel covering 196-229 genes associated with both syndromic and nonsyndromic hearing loss. 2, 3, 4

Recommended Gene Panel Components

The modern standard includes:

• Core nonsyndromic hearing loss genes: GJB2, GJB6, GJB3, KCNQ4, TECTA, ACTG1, STRC, COCH, EYA4 5, 2
• Syndromic hearing loss genes: SLC26A4 (Pendred syndrome), COL2A1 (Stickler syndrome), COL11A1, ABHD12 5, 2
• Mitochondrial genes: MT-RNR1 (12S rRNA), MT-TS1 (tRNA-Ser), particularly the A1555G mutation associated with aminoglycoside sensitivity 1, 5
• Copy number variation analysis: Essential for detecting deletions in genes like STRC 4

Evidence Supporting Comprehensive Panels

Recent studies demonstrate that comprehensive NGS panels achieve:

• Diagnostic yields of 23-41% in adult-onset sensorineural hearing loss 2, 3
• Sensitivity and specificity >99% for clinical use 3
• Identification of previously unrecognized syndromic associations in 20% of genetically diagnosed cases, including Stickler syndrome and PHARC syndrome 2

Advanced Testing Considerations

If standard NGS panel testing is negative, consider whole-genome sequencing (WGS) to identify variants missed by exome-based approaches. 4

WGS can detect:

• Cryptic splice variants in genes like EYA1 and CDH23 4
• Structural variants and copy number changes 4
• Transposable element insertions (e.g., Alu insertions in SLC17A8) 4
• Cis-regulatory variants affecting gene expression 4

In a recent cohort, WGS identified causative variants in 26% of families where previous testing had failed 4

Critical Pre-Test Evaluation

Before ordering genetic testing, exclude environmental causes through targeted history:

• CMV testing should be performed, though interpretation requires caution—negative CMV antibodies in early infancy may exclude CMV-related hearing loss 1
• Document exposure to ototoxic drugs (aminoglycosides, loop diuretics, chemotherapy agents) 6, 7
• Rule out acoustic trauma, meningitis, ECMO exposure, and hypoxia 1, 7

Perform a thorough physical examination to identify occult syndromic features that would guide gene-specific testing:

• Visual abnormalities: heterochromia irides, retinitis pigmentosa, early cataracts 1, 6
• Cardiac evaluation: document any syncope, arrhythmias, or prolonged QT interval (Jervell and Lange-Nielsen syndrome carries sudden death risk) 1, 6
• Renal assessment: inquire about hematuria, proteinuria (Alport syndrome) 1, 6
• Pigmentary changes: white forelock, premature graying, abnormal skin pigmentation (Waardenburg syndrome) 1, 6
• Facial/cervical features: preauricular pits, branchial cysts (branchio-oto-renal syndrome) 1, 6

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 1, 6, 2
• A negative GJB2 test does not exclude genetic etiology—it only rules out the most common cause 1
• Absence of family history is not reassuring—autosomal recessive inheritance commonly presents without family history 1

Clinical Utility of Genetic Diagnosis

Identifying the genetic cause enables:

• Accurate genetic counseling regarding recurrence risk 2, 8
• Prognostic information about progression patterns 2, 8
• Detection of associated systemic manifestations requiring surveillance 2, 8
• Determination of candidacy for specific therapies including cochlear implantation 8
• Prevention strategies (e.g., avoiding aminoglycosides in patients with mitochondrial mutations) 1