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July 21, 2026CirculationOpen Access

Titin Missense Variants as a Cause of Familial Dilated Cardiomyopathy

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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

FDFernándo DomínguezLLLaura LalagunaIMInés Martínez-Martín

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Key expert perspectives

Captured external expert commentary on this paper, strongest first. Original sources are linked where available.

OAOyediran AkinrinadeResearcher, Institute of Clinical Medicine, Helsinki

“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”

Helsinki University Central HospitalNews Coverage

Overview

Randomized trial identifies TTN missense variants causing dilated cardiomyopathy, suggesting novel genetic insights in affected families.

Key Points

  • To investigate the role of TTN missense variants in familial dilated cardiomyopathy (DCM) and evaluate their pathogenicity.
  • Family assessment with exome sequencing to identify shared genetic variants in families with DCM.
  • Functional evaluation using induced pluripotent stem cells to study contraction amplitude in variant carriers.
  • In silico predictions for variant deleteriousness using bioinformatics tools.
  • Identified TTN missense variant p.Cys3892Ser in a Spanish family with an 86% DCM penetrance among carriers.
  • Variant p.Cys3892Ser associated with decreased cardiac contraction amplitude in induced pluripotent stem cell-derived cardiomyocytes (P=0.0001).
  • Both TTN variants reported are novel, not found in genotyping databases like gnomAD.

PICO

P
Population
40 members from a Spanish and a Danish family evaluated for familial dilated cardiomyopathy and TTN missense variants.
E
Exposure / Comparator
TTN missense variants (p.Cys3892Ser and p.Cys3575Arg) vs Noncarriers
O
Primary Outcome
Dilated cardiomyopathy — LOD score 3.96

Main Result

Effect estimate: LOD score 3.96

Absolute Event Rate: 86% vs 0%

Cite This Study

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.

synapsesocial.com/papers/6a5fe255bd312198529349a1https://doi.org/10.1161/circulationaha.122.062833
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