TMTC2 and Sensorineural Hearing Loss

This summary details the association between TMTC2 (HGNC:25440) and sensorineural hearing loss disorder (MONDO_0020678). Two independent studies provide evidence for this association, one reporting a family dyad (PMID:29671961) and the other describing a large multigeneration family with 19 affected individuals (PMID:27311106).

The clinical validity of the association is supported by robust genetic evidence. The larger study demonstrated autosomal dominant inheritance with convincing segregation in a six‐generation family, where 19 affected relatives carried a fully penetrant sequence variant. An independent study replicated the finding in a related family dyad, further bolstering the gene–disease relationship (PMID:27311106; PMID:29671961).

Genetic evidence highlights the presence of a recurrent variant, reported as rs35725509 in both studies. Although a formal HGVS coding change was not provided in the reports, this recurrent finding in independent cohorts supports the pathogenic role of TMTC2 in sensorineural hearing loss. The segregation analysis, combined with the replication of the variant in distinct populations, confers a strong weight to the evidence.

Functionally, while detailed experimental studies remain limited, the observed genotype‐phenotype correlation and successful clinical outcomes following cochlear implantation underscore the biological relevance of the TMTC2 variant. The absence of extensive functional model data suggests that functional evidence is currently limited, yet the clinical findings provide indirect support for a haploinsufficiency or dominant mechanism.

In summary, both the segregation data from a large, multigeneration family and independent confirmation in a family dyad converge to substantiate a strong gene–disease association. Additional functional studies may further elucidate the pathogenic mechanism, but current evidence is sufficient to support the clinical utility of TMTC2 in the diagnostic evaluation of sensorineural hearing loss.

Key Take‑home sentence: TMTC2 is strongly implicated in autosomal dominant sensorineural hearing loss disorder, a finding that enhances diagnostic decision‑making and may guide future therapeutic strategies.

References

• JAMA otolaryngology-- head & neck surgery • 2016 • Association of TMTC2 With Human Nonsyndromic Sensorineural Hearing Loss PMID:27311106
• Molecular genetics & genomic medicine • 2018 • TMTC2 variant associated with sensorineural hearing loss and auditory neuropathy spectrum disorder in a family dyad PMID:29671961

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