TPM1 – Left Ventricular Noncompaction Cardiomyopathy

Left ventricular noncompaction cardiomyopathy (LVNC; MONDO:0018901) is a primary genetic cardiomyopathy characterized by a bilayered myocardium with excessive trabeculations and deep intertrabecular recesses. TPM1 encodes α-tropomyosin, a key sarcomere thin filament component, and heterozygous variants have been implicated in autosomal dominant LVNC.

In a cohort of 58 unrelated LVNC probands screened for 17 sarcomere genes, TPM1 variants were identified in 23 of 56 tested cases (41%) and transmitted in an autosomal dominant manner in 18 families ([PMID:20530761]). Cardiological family screening of 194 relatives revealed 17 mutation carriers, of whom 9 manifested LVNC and 8 were nonpenetrant, supporting segregation of TPM1 variants with disease ([PMID:20530761]).

A distinct TPM1 missense substitution, c.109A>G (p.Lys37Glu), was found in three affected members of a familial LVNC pedigree with sudden death, absent in 200 controls, and predicted to alter mRNA splicing and tropomyosin charge ([PMID:20965760]).

Overall, TPM1 variant spectrum in LVNC comprises predominantly heterozygous missense substitutions (e.g., c.109A>G (p.Lys37Glu) [PMID:20965760], c.479G>A (p.Arg160His) [PMID:20530761], c.533G>A (p.Arg178His) [PMID:30188508], c.713G>A (p.Arg238Gln) [PMID:32183154], c.823G>C (p.Asp275His) [PMID:26025024]) with no recurrent founder allele identified. Allele frequencies reach up to 41% in screened cohorts, with penetrance influenced by age and possibly variant position.

Functional studies of patient-derived induced pluripotent stem cell cardiomyocytes harboring c.533G>A (p.Arg178His) demonstrate mislocalization of tropomyosin, sarcomere disarray, and impaired calcium transients, recapitulating LVNC pathology ([PMID:30188508]). In vitro motility assays and structural analyses of other cardiomyopathy-associated TPM1 mutants further support a dominant-negative mechanism disrupting thin filament regulation.

Taken together, extensive case series, family segregation, and concordant functional data fulfill ClinGen criteria for a Strong gene–disease association. Genetic testing for TPM1 missense variants should be incorporated into LVNC diagnostic panels, and positive findings can guide family screening, risk stratification, and management.

References

• Circulation. Cardiovascular genetics • 2010 • The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. PMID:20530761
• Molecular genetics and metabolism • 2011 • Identification of a novel TPM1 mutation in a family with left ventricular noncompaction and sudden death. PMID:20965760
• Pediatric research • 2018 • Sarcomere gene variants act as a genetic trigger underlying the development of left ventricular noncompaction. PMID:30188508

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