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 in a specific geographic region?

Genetic Testing for Young Adults with Nonsyndromic Sensorineural Hearing Loss

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, followed by a comprehensive hearing loss gene panel if GJB2 testing is negative. 1

Initial Testing Algorithm

First-Line: GJB2 (Connexin 26) Testing

• GJB2 mutation screening by sequence analysis should be obtained first in patients presenting as simplex cases (isolated cases without family history of hearing loss). 1
• A positive GJB2 result can avoid other expensive and potentially invasive tests, as GJB2 mutations are the most common cause of genetic deafness in the United States. 1
• GJB2 accounts for a substantial proportion of nonsyndromic hearing loss cases, even in the absence of family history, since autosomal recessive inheritance can present without affected relatives. 1

Second-Line: Comprehensive Gene Panel

• If GJB2 testing is negative, proceed to a comprehensive hearing loss gene panel covering both syndromic and nonsyndromic hearing loss genes. 1, 2
• Modern next-generation sequencing panels provide diagnostic yields of approximately 40% for hereditary hearing loss and over 20% for adult-onset cases. 2, 3
• Comprehensive panels now include 196-229 genes associated with hearing loss, covering the genetic heterogeneity of this condition. 3

Additional Considerations

Environmental Cause Exclusion

• CMV testing should be performed to exclude congenital CMV infection, though this is more relevant in early childhood presentations. 1
• Document exposure history including ototoxic drugs, acoustic trauma, and perinatal risk factors to rule out environmental causes. 1, 4

Mitochondrial DNA Testing

• Consider testing for mitochondrial mutations (A1555G and A7445G) if there is any history of aminoglycoside exposure or if the pattern suggests maternal inheritance, but only after GJB2 mutations are excluded. 1
• These mitochondrial variants are associated with aminoglycoside-induced hearing loss and some familial cases. 1

Important Caveats

Interpretation Pitfalls

• A negative genetic test does NOT mean the hearing loss is not genetic. This is a critical distinction that must be conveyed to patients. 1
• Approximately 30% of patients with hearing loss will have no obvious etiology on initial evaluation, but many still have an underlying genetic cause. 1
• The probability that hearing loss is genetic varies based on ethnicity and the number of unaffected siblings in the family. 1

Panel Selection Considerations

• Ensure the chosen panel includes copy number variant (CNV) analysis, as deletions/duplications (particularly in STRC gene) are common but technically challenging to detect. 1
• 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. 1
• Laboratories specializing in hearing loss genetics may have superior approaches for analyzing difficult genomic regions. 1

Syndromic Features Assessment

• Systematically evaluate for syndromic features even in apparently isolated cases, as 20% of genetically diagnosed adults have unrecognized syndromic associations. 3
• Screen for visual abnormalities (retinitis pigmentosa, early cataracts), cardiac symptoms (prolonged QT, syncope), renal abnormalities, thyroid disease, and integumentary changes. 1, 4

Emerging Technologies

Whole Exome/Genome Sequencing

• Consider whole exome sequencing (ES) or whole genome sequencing (WGS) if comprehensive panel testing is negative and clinical suspicion for genetic etiology remains high. 1
• WGS can identify cryptic splice variants, structural variants, and regulatory variants not detected by standard panels, with diagnostic rates of 26% in previously unsolved cases. 5
• WGS has particular advantages for detecting STRC deletions, mitochondrial variants, and Alu insertions that may be missed by exome-based approaches. 5