TPM1 – Hypertrophic Cardiomyopathy

Tropomyosin 1 (TPM1) variants are associated with autosomal dominant hypertrophic cardiomyopathy (HCM). Multiple family‐based studies have identified rare TPM1 missense mutations segregating with HCM phenotypes, including both de novo and inherited alleles. Clinical linkage analysis and molecular autopsy demonstrate robust cosegregation of TPM1 mutations with HCM in large pedigrees, supporting a strong gene–disease relationship.

Inheritance follows an autosomal dominant pattern with incomplete age‐dependent penetrance. In one large Spanish‐American kindred, the TPM1 V95A (c.284T>C (p.Val95Ala)) mutation cosegregated with HCM in 26 affected individuals, including 13 sudden cardiac deaths by age 40 (PMID:11136687). A separate family harbored a de novo L185R (c.610T>G (p.Leu185Arg)) change, which was absent from 400 controls and was present in multiple affected siblings and their father (PMID:12423715).

Case reports and series describe a spectrum of TPM1 variants—most commonly missense changes—occurring in unrelated probands with HCM. c.284T>C (p.Val95Ala) and c.610T>G (p.Leu185Arg) are the most frequently reported. No deep‐intronic or structural variants have been implicated. Founder effects have been noted for D175N in Finnish cohorts.

Functional assays reveal that HCM‐linked TPM1 mutations alter thin filament regulation. The V95A mutant increases Ca2+ sensitivity of actomyosin MgATPase by 40–50%, reduces unloaded in vitro motility velocity by 5%, and prolongs myosin‐bound states, suggesting aberrant cross‐bridge kinetics (PMID:11136687). c.610T>G (p.Leu185Arg) disrupts troponin‐T interactions and enhances arrhythmogenic susceptibility (PMID:12423715).

Segregation of TPM1 mutations in multiple large families, concordant functional data across independent laboratories, and recurrence of key alleles establish a Strong clinical validity per ClinGen criteria. Genetic evidence is capped by numerous probands and extensive segregation (Strong). Functional studies demonstrate mechanistic plausibility (Moderate).

Key take‐home: TPM1 missense variants cause autosomal dominant HCM via thin filament dysregulation; genetic testing for TPM1 should be integrated into HCM panels to inform cascade screening and guide preventive management.

References

• Circulation • 2001 • Hypertrophic cardiomyopathy caused by a novel alpha-tropomyosin mutation (V95A) is associated with mild cardiac phenotype, abnormal calcium binding to troponin, abnormal myosin cycling, and poor prognosis. PMID:11136687
• The American Journal of Cardiology • 2002 • A novel TPM1 mutation in a family with hypertrophic cardiomyopathy and sudden cardiac death in childhood. PMID:12423715

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