FAM136A – Meniere Disease

This summary details the association between FAM136A and Meniere disease. Familial studies have identified a heterozygous nonsense variant, c.547C>T (p.Gln183Ter) (PMID:25305078), in a Spanish family presenting with autosomal‐dominant inheritance of Meniere disease. Affected family members exhibited sensorineural hearing impairment and tinnitus, key clinical features of the condition. The variant leads to a premature stop codon, suggesting a loss‐of‐function mechanism that likely contributes to the disease pathogenesis.

Genetic investigations have been extended beyond the initial case report. Multi‐patient studies in sporadic Meniere disease cohorts have detected rare variants in FAM136A among other candidate genes, supporting the putative role of FAM136A in the broader disease context (PMID:32038468, PMID:33136635). Although the number of probands is limited, the segregation observed in consecutive generations adds weight to the genetic evidence.

Segregation analysis in the familial study indicated that the variant co‐segregates with disease, with two additional affected relatives identified in the reported family (PMID:25305078). This provides a sound basis for inferring autosomal dominant inheritance for this gene–disease relationship. In addition, the screening of affected individuals in independent cohorts has lent further support to the association by revealing similar rare coding variants in FAM136A in sporadic cases.

Functional assessments provide concordant evidence that the molecular consequence of the c.547C>T (p.Gln183Ter) mutation results in decreased transcript levels in patient-derived lymphoblastoid cells. Immunoblotting confirmed the reduction in protein expression, which is consistent with a loss‐of‐function effect. These functional studies corroborate the genetic data and emphasize the mechanistic plausibility of FAM136A involvement in the disease pathophysiology (PMID:25305078).

The integration of genetic and functional findings supports a moderate level of clinical validity for the association between FAM136A and Meniere disease. Despite the limited number of familial cases, the combination of segregation data, molecular consequences of the variant, and supportive findings in multi-patient cohorts underline its potential utility as a diagnostic marker. Further studies with larger cohorts could reinforce and extend these findings.

Key take‑home: FAM136A is emerging as a promising candidate gene for Meniere disease with both familial and sporadic evidence supporting its role, making it valuable for diagnostic decision‑making and potential commercial genetic testing applications.

References

• Human molecular genetics • 2015 • Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere's disease PMID:25305078
• Frontiers in neurology • 2019 • Rare Variants of Putative Candidate Genes Associated With Sporadic Meniere’s Disease in East Asian Population PMID:32038468
• Ear and hearing • 2020 • Burden of Rare Variants in the OTOG Gene in Familial Meniere's Disease PMID:33136635

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