Key result
Rare TTN variants are identified in sudden cardiac death, implicating novel missense mutations.
Observational (n=1,126)
The high prevalence of rare TTN variants across multiple SCD-related pathologies underscores their potential role as disease modulators, though functional studies and family segregation remain necessary to confirm pathogenicity.
Rare TTN variants may modulate sudden cardiac death risk; leaves open pathogenicity pending functional and segregation studies.
A leading cause of death in western countries is sudden cardiac death, and can be associated with genetic disease. Next-generation sequencing has allowed thorough analysis of genes associated with this entity, including, most recently, titin. We aimed to identify potentially pathogenic genetic variants in titin. A total of 1126 samples were analyzed using a custom sequencing panel including major genes related to sudden cardiac death. Our cohort was divided into three groups: 432 cases from patients with cardiomyopathies, 130 cases from patients with channelopathies, and 564 post-mortem samples from individuals showing anatomical healthy hearts and non-conclusive causes of death after comprehensive autopsy. None of the patients included had definite pathogenic variants in the genes analyzed by our custom cardio-panel. Retrospective analysis comparing the in-house database and available public databases also was performed. We identified 554 rare variants in titin, 282 of which were novel. Seven were previously reported as pathogenic. Of these 554 variants, 493 were missense variants, 233 of which were novel. Of all variants identified, 399 were unique and 155 were identified at least twice. No definite pathogenic variants were identified in any of genes analyzed. We identified rare, mostly novel, titin variants that seem to play a potentially pathogenic role in sudden cardiac death. Additional studies should be performed to clarify the role of these variants in sudden cardiac death.
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Campuzano et al. (2015) conducted an observational in Sudden Cardiac Death / Cardiomyopathies / Channelopathies (n=1,126). Presence of rare TTN (titin) gene variants was evaluated on Identification and frequency of rare potentially pathogenic genetic variants in the TTN gene. Next-generation sequencing identified 554 rare TTN variants (282 novel), mostly missense, suggesting a potentially pathogenic or modulating role in sudden cardiac death.
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