The VUS problem in pediatric hearing loss just got harder
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A pathogenic OTOF variant in combination with a variant of unknown significance provides valuable information for consideration; however, this does not provide confirmation of a genetic disorder.
—Scott Nass, MD
A child has the classic phenotype of OTOF-related auditory neuropathy, but genetic testing finds one likely pathogenic OTOF variant and a second variant of uncertain significance (VUS).
This scenario has been documented. Two individuals carried OTOF c.5374C>T (p.Arg1792Cys) with a second OTOF VUS, and family testing confirmed the variants were in trans. At least one had auditory neuropathy spectrum disorder.[]
The distinction now has treatment implications. OTOF-related hearing loss requires biallelic pathogenic or likely pathogenic variants for molecular confirmation, while a VUS does not establish the diagnosis.[]
“A pathogenic OTOF variant in combination with a variant of unknown significance provides valuable information for consideration; however, this does not provide confirmation of a genetic disorder,” says Scott Nass, MD, a board-certified family medicine physician.
So what should clinicians do when the phenotype fits OTOF-related disease but one allele remains uncertain?
Related: Hearing gains are not the endpoint: What should clinicians watch after OTOF gene therapy?Variant of uncertain significance
A VUS is not a molecular diagnosis. Neither two OTOF VUSs nor one pathogenic OTOF variant plus one VUS establishes or excludes OTOF-related hearing loss.[] A diagnosis requires biallelic pathogenic or likely pathogenic variants consistent with the phenotype.
That creates a difficult scenario. A child has profound congenital hearing loss, preserved outer hair cell function, abnormal auditory brainstem response, and a phenotype strongly suggestive of OTOF-related auditory neuropathy. Sequencing identifies one clearly pathogenic OTOF variant and a second VUS.
“Unless there are other data that support reclassification from VUS to another category, the clinician should maintain the VUS status,” Dr. Nass says.
Related: Hearing gains are not the endpoint: What should clinicians watch after OTOF gene therapy?Consequences of clinical uncertainty
The distinction between “suggestive of OTOF” and “molecularly confirmed OTOF” now has therapeutic consequences. The FDA indication for Otarmeni specifically requires molecularly confirmed biallelic OTOF variants.[]
The clinical consequences of uncertainty deserve attention.
A 2026 systematic review of 45 articles found that VUS findings affected at least some care decisions in 67% of studies.[] The review identified three patterns: VUS findings were treated as benign, weak positives, or pathogenic. The authors noted substantial heterogeneity between studies.
Establishing a diagnosis
“Begin by assessing the full clinical picture of the individual child (ie, the type and extent of hearing loss, audiologic test results, age of onset of symptoms, etc.) to identify similarities in both the degree of similarity of this clinical picture with previously described OTOF-related hearing losses as well as the variant’s characteristics,” Dr. Nass advises.
Parental testing can determine whether the two variants are in trans, supporting an autosomal recessive model. The laboratory report should then be reviewed alongside population frequency, segregation, phenotype, predicted molecular consequence, published cases, and functional data. Hearing-loss-specific criteria from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology are preferable to generic interpretation alone.[][]
In a ClinGen Hearing Loss Variant Curation Expert Panel study, 75% of 157 evaluated variants had single or multiple variants of VUS submissions or conflicting interpretations before expert review.[]
Applying hearing-loss-specific criteria resolved 24% of VUS classifications and 69% of discordant variants into benign, likely benign, likely pathogenic, or pathogenic classifications.
“Review the frequency at which the variant appears in large population databases. Determine if it occurs within a ‘hot spot’ region of the gene. Assess the potential impact that the variant has on the resulting protein product. Identify previous reports of similar or identical variants occurring in clinically affected individuals,” Dr. Nass suggests.
Related: 4 major shifts in genetic pediatric hearing loss care: A historical look-back