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Autosomal‐dominant hypertrophic cardiomyopathy (HCM) is most often caused by pathogenic variants in sarcomeric genes, including the gene encoding cardiac troponin I, TNNI3. HCM is characterized by asymmetric left ventricular hypertrophy, myocyte disarray, and increased risk of sudden cardiac death, encompassing the phenotype Hypertrophic Cardiomyopathy.
Genetic screening of 748 unrelated HCM families identified TNNI3 mutations in 3.1% of probands, clustering in exons 7–8, with 100 mutation carriers across 23 families and 48 clinically affected relatives, demonstrating 48% penetrance and variable expressivity (PMID:15607392). Segregation analyses confirmed autosomal‐dominant transmission with age at diagnosis spanning the second to eighth decades (PMID:15607392).
Case reports and series describe over 30 distinct TNNI3 variants, predominantly missense changes in the inhibitory and C‐terminal regions. For example, a de novo NM_000363.5:c.583A>T (p.Ile195Phe) in a 14‐year‐old with nonobstructive HCM underscores the role of novel heterozygous alleles in pediatric disease (PMID:38548731). Founder mutations such as c.61C>T (p.Arg21Cys) recur in specific populations and confer malignant HCM with early sudden cardiac death (PMID:32885985).
The variant spectrum includes missense substitutions (e.g., c.433C>G (p.Arg145Gly)), small in‐frame deletions, and rare splice alterations, all absent in large control cohorts. No truncating variants have been reported, supporting a dominant‐negative or poison‐peptide mechanism rather than haploinsufficiency.
Functional assays of recombinant troponin complexes show that HCM‐linked TNNI3 mutants, including R145G and R162W, increase Ca2+ sensitivity of actomyosin ATPase and thin‐filament sliding, impair relaxation, and blunt the desensitizing effect of PKA‐mediated Ser23/24 phosphorylation (PMID:10806205, PMID:14654368). Transgenic mice expressing R145G cTnI develop cardiomyocyte disarray, fibrosis, hypercontractility, diastolic dysfunction, and early lethality in a dose‐dependent manner, faithfully recapitulating human HCM (PMID:11055985).
Mechanistically, TNNI3 mutations perturb the inhibitory interaction between troponin I and actin–tropomyosin, enhancing Ca2+ affinity and cross‐bridge cycling, leading to diastolic dysfunction, myocardial hypertrophy, and fibrosis. Rescue experiments in double‐transgenic models highlight critical TnI–TnT interactions in β‐adrenergic regulation and suggest therapeutic targets for troponin cardiomyopathies (PMID:20551314).
There is no evidence for frequent somatic TNNI3 mutations in sporadic HCM, and conflicting reports are limited. Overall, the association between TNNI3 and HCM is Definitive based on multiple unrelated families, robust segregation, and concordant functional models.
Key Take‐home: Pathogenic TNNI3 variants cause definitive autosomal‐dominant HCM; genetic testing guides diagnosis, family screening, and risk stratification.
Gene–Disease AssociationDefinitiveMultiple independent cohorts, segregation in 23 families, and concordant functional models Genetic EvidenceStrong3.1% of 748 families with 100 carriers, 48 affected relatives; autosomal dominant segregation (PMID:15607392) Functional EvidenceStrongIn vitro and transgenic mouse studies demonstrate increased Ca2+ sensitivity, diastolic dysfunction, and hypertrophy (PMIDs:10806205, 11055985) |