Why the study?
Although truncating variants in TTN are the main genetic cause of dilated cardiomyopathy, the role of rare missense variants in TTN as a cause of DCM remains unknown.
Population
Two families with DCM (one Spanish kindred of 36 members and one Danish family)
Comparison
TTN missense variant carriers vs noncarriers and wild-type controls
Design
Family-based genetic and in vitro translational study
Key result
Rare missense variants affecting a conserved cysteine in the TTN gene (p.Cys3892) co-segregated with familial dilated cardiomyopathy (LOD score 3.96) and caused deficient cardiomyocyte contraction.
Authors
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Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“In this study, we provide data that show that TTN missense and NFS-INDEL variants are not significantly enriched in a large group of DCM patients compared to control populations and should therefore be classified as likely benign in a clinical diagnostic setting. Nevertheless, it cannot be excluded that some rare TTN missense variants might have a modifier effect on the phenotype”
Randomized trial identifies TTN missense variants causing dilated cardiomyopathy, suggesting novel genetic insights in affected families.
Effect estimate: LOD score 3.96
Absolute Event Rate: 86% vs 0%
Domínguez et al. (2023) conducted a letter in Familial Dilated Cardiomyopathy (n=40). TTN missense variants (p.Cys3892Ser and p.Cys3575Arg) vs. Noncarriers was evaluated on Dilated cardiomyopathy (LOD score 3.96). Rare missense variants affecting a conserved cysteine in the TTN gene (p.Cys3892) co-segregated with familial dilated cardiomyopathy (LOD score 3.96) and caused deficient cardiomyocyte contraction.