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Titin (TTN; HGNC:12403) encodes the largest human sarcomeric protein, spanning half the length of the cardiac myofilament and contributing to passive tension and mechanosignaling. While TTN truncating variants are a well-established cause of dilated cardiomyopathy, subtler TTN missense and splice variants have been increasingly reported in hypertrophic cardiomyopathy (HCM) cohorts, suggesting a broader role in sarcomere dysfunction (PMID:22335739; PMID:28223422). HCM, characterised by left ventricular hypertrophy and myocyte disarray, follows an autosomal dominant inheritance pattern when linked to sarcomere gene mutations.
Targeted next-generation sequencing of 231 HCM probands identified rare TTN variants in approximately 1% of cases, including both missense and truncating alleles, though overall TTN truncating variant (TTNtv) prevalence did not exceed control frequencies (PMID:22335739; PMID:28822653). In a Chinese pedigree with HCM, a novel heterozygous missense variant, c.20233C>T (p.Arg6745Cys), was found in the proband and two additional affected relatives, segregating with disease in three generations (PMID:39895828). This supports an autosomal dominant mode with reduced penetrance.
Segregation analysis in that family showed c.20233C>T present in three affected members and absent in six unaffected relatives, yielding two additional segregations beyond the proband. Further case reports, including c.23965C>T (p.Arg7989Cys) and other TTN missense changes, expand the list of variants co-occurring with HCM phenotypes, though systematic co-segregation has been limited to small kindreds (PMID:39895828).
The TTN variant spectrum in HCM is dominated by missense changes located in A-band Fn3 and PEVK regions; truncating variants are rare and occur without significant enrichment compared to controls (PMID:28822653). Large cohorts have catalogued over 40 rare TTN missense variants subject to bioinformatic prediction of deleteriousness, though classification remains challenging (PMID:26567375).
Functional studies provide mechanistic support. Crystal structures of A-band Fn3 domains harboring HCM-linked variants (e.g., p.Arg27839Gln) exhibit reduced thermal stability, consistent with misfolding (PMID:37549721). Single-molecule and co-sedimentation assays demonstrate Ca2+-dependent binding of the N2A unique sequence to F-actin, implicating altered titin–actin interactions in sarcomeric stiffness and contractility (PMID:30275509).
Conflicting evidence tempers these findings: TTNtv frequency in HCM approximates that in healthy controls, and many rare missense variants fail to co-segregate or reclassify as benign upon ACMG guideline re-evaluation (PMID:28822653; PMID:26567375). Oligogenic inheritance models and variant modifiers further complicate clear monogenic attribution.
In summary, TTN variants—predominantly missense changes—are emerging contributors to HCM, supported by limited co-segregation and concordant in vitro functional data. While current evidence warrants a ClinGen Moderate gene–disease association, further large-scale familial studies and standardized variant classification are essential. Key take-home: TTN screening may identify pathogenic or modifying variants in HCM patients, guiding risk stratification and family counseling.
Gene–Disease AssociationModerateMultiple independent HCM probands with rare TTN variants and limited co-segregation evidence Genetic EvidenceLimited6 probands with TTN variants; segregation limited to small families Functional EvidenceModerateIn vitro structural and binding assays demonstrate variant-induced domain destabilization and altered titin–actin interactions |