TNNI3 – Restrictive Cardiomyopathy

Restrictive cardiomyopathy (RCM) is a rare myocardial disorder characterized by impaired ventricular filling and biatrial enlargement due to diastolic dysfunction. Pathogenic variants in the cardiac troponin I gene (TNNI3; HGNC:11947) have been repeatedly implicated in autosomal dominant RCM (MONDO:0005201), with de novo and familial missense mutations clustering in conserved functional domains of cTnI. Clinical presentations range from infancy to adulthood, often progressing to heart failure and requiring transplantation.

Genetic evidence for TNNI3 involvement in RCM includes identification of pathogenic variants in at least 13 unrelated probands across five cohort studies. In a large family with mixed RCM and hypertrophic cardiomyopathy phenotypes, a novel missense variant c.533A>G (p.Lys178Arg) cosegregated with disease in 6 of 15 affected individuals (lod 4.8) ([PMID:12531876]). Among 12 pediatric idiopathic RCM cases, truncating and missense TNNI3 variants were found in 4 patients (33%) ([PMID:18467357]). Whole-exome sequencing of five sporadic pediatric RCM patients revealed TNNI3 variants in all cases ([PMID:29176140]), and a Chinese family demonstrated cosegregation of NM_000363.5:c.448T>C (p.Ser150Pro) in 4 affected relatives ([PMID:28031081]). A recurring de novo hotspot, c.611G>A (p.Arg204His), has been reported in multiple isolated cases, confirming its pathogenicity.

Inheritance is predominantly autosomal dominant, with one reported autosomal recessive presentation: a consanguineous kindred carrying homozygous NM_000363.4:c.586G>C (p.Asp196His), where heterozygous carriers were asymptomatic ([PMID:30953456]). Segregation analysis supports high penetrance in heterozygotes, and de novo occurrence further implicates TNNI3 variants in disease causation.

Variant spectrum is dominated by missense substitutions (e.g., p.Arg204His, p.Ser150Pro, p.Arg170Trp, p.Arg192Cys) affecting the inhibitory and C-terminal regions of cTnI, with >20 distinct missense changes documented. Protein-truncating variants (e.g., p.Glu84Ter, p.Asp180fs) account for at least four RCM families, indicating that both dominant-negative and haploinsufficient mechanisms may underlie pathology.

Functional and experimental studies demonstrate that RCM-associated TNNI3 mutations increase myofilament Ca²⁺ sensitivity and impair relaxation. Actomyosin ATPase assays and skinned fiber experiments for five RCM variants (L144Q, R145W, A171T, K178E, R192H) revealed gains in Ca²⁺ sensitivity (ΔpCa₅₀ up to 0.47) and reduced inhibitory function of cTnI ([PMID:15961398]). Patient-derived iPSC models harboring c.508C>T (p.Arg170Trp) in engineered heart tissues recapitulated diastolic dysfunction and were rescued by CRISPR-mediated correction or wild-type TNNI3 overexpression ([PMID:38193576], [PMID:38497452]).

While most TNNI3 variants cause RCM, several alleles (e.g., p.Arg170Gln, p.Leu144His) manifest overlapping hypertrophic features, and some truncating variants have been reported in dilated cardiomyopathy, underscoring phenotype variability. No high-quality studies have refuted the TNNI3–RCM association, but genotype–phenotype correlations remain complex.

Integration of genetic, segregation, and functional data yields a Strong ClinGen classification for TNNI3 in RCM, supported by 13 probands, multi-family segregation, and concordant functional assays. Genetic testing for TNNI3 should be included in RCM diagnostic panels, family screening is critical for early detection, and emerging gene-editing strategies hold therapeutic promise.

References

• The Journal of clinical investigation • 2003 • Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. PMID:12531876
• Heart (British Cardiac Society) • 2008 • Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes. PMID:18467357
• Chinese medical journal • 2017 • Role of Whole-exome Sequencing in Phenotype Classification and Clinical Treatment of Pediatric Restrictive Cardiomyopathy. PMID:29176140
• Chinese medical sciences journal • 2016 • Restrictive Cardiomyopathy Resulting from a Troponin I Type 3 Mutation in a Chinese Family. PMID:28031081
• BMC medical genetics • 2019 • A case report of recessive restrictive cardiomyopathy caused by a novel mutation in cardiac troponin I (TNNI3). PMID:30953456
• Development, growth & differentiation • 2024 • Gene correction and overexpression of TNNI3 improve impaired relaxation in engineered heart tissue model of pediatric restrictive cardiomyopathy. PMID:38193576
• Journal of the American Heart Association • 2024 • Impaired Relaxation in Induced Pluripotent Stem Cell-Derived Cardiomyocytes with Pathogenic TNNI3 Mutation of Pediatric Restrictive Cardiomyopathy. PMID:38497452
• The Journal of biological chemistry • 2005 • Mutations in human cardiac troponin I that are associated with restrictive cardiomyopathy affect basal ATPase activity and the calcium sensitivity of force development. PMID:15961398

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