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. 2025 Apr;18(2):e004982.
doi: 10.1161/CIRCGEN.124.004982. Epub 2025 Feb 19.

Analysis of TTN Truncating Variants in >74 000 Cases Reveals New Clinically Relevant Gene Regions

Matteo Vatta #  1 , Ellen Regalado #  1 , Michael Parfenov #  1 , Dan Swartzlander  1 , Andrea Nagl  1 , Meghan Mannello  1 , Rachel Lewis  1 , Daniel Clemens  1 , John Garcia  1 , Rachel E Ellsworth  1 , Ana Morales  1 , Yi-Lee Ting  1 , Swaroop Aradhya  1   2
Affiliations

Analysis of TTN Truncating Variants in >74 000 Cases Reveals New Clinically Relevant Gene Regions

Matteo Vatta et al. Circ Genom Precis Med. 2025 Apr.

Abstract

Background: Truncating variants (TTNtvs) in the titin (TTN) gene have been associated with cardiomyopathies or arrhythmias (C/A) and autosomal recessive neuromuscular diseases (NM). However, the clinical significance of TTNtvs across the entire coding sequence of TTN has not been comprehensively assessed. The purpose of this study was to examine the burden of TTNtvs in C/A and NM cases compared with controls in the genome aggregation database.

Methods: This was a retrospective study of probands who underwent multigene testing (49 740 C/A panel, 24 514 NM panel) that included TTN from November 2017 to October 2021. Burden testing was performed using controls in the genome aggregation database v3.1.2 database, and the analysis was stratified by exon/band location and exon usage in cardiac or skeletal muscle. Frequency and odds ratio of TTNtv alleles in C/A or NM cases and genome aggregation database controls were measured.

Results: There were 2446 (4.9%) C/A and 482 (2.0%) NM cases with 2446 and 528 TTNtv alleles, respectively. TTNtvs in all bands were significantly enriched in both C/A and NM cases compared with controls. A significant enrichment of TTNtvs in C/A was observed for exon 358 of the M-band (odds ratio, 2.55 [95% CI, 1.85-3.54]) but not the other M-band exons.

Conclusions: In the largest single-site cohort of C/A and NM cases with TTNtvs, an enrichment of TTNtvs across TTN was observed. These findings expand the clinically relevant regions of TTN.

Keywords: alleles; arrhythmias, cardiac; cardiomyopathies; exons; neuromuscular diseases.

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Conflict of interest statement

All authors are current employees of Labcorp (formerly Invitae Corporation) and former employees and shareholders of Invitae Corp. Invitae provided salary support for this project.

Figures

Figure.
Figure.
Distribution of TTN variant (TTNtv) alleles by sarcomere band and proportion spliced-in (PSI). Distribution of truncating TTNtv alleles by sarcomere band and PSI,, group compared with genome aggregation database (gnomAD) v3.1.2 controls (n=922 TTNtv alleles). Data for heart tissue in cardiomyopathy or arrhythmia (C/A) cases (n=2446 TTNtv alleles) is shown in A and for skeletal muscle tissue in neuromuscular disease (NM) cases (n=528 TTNtv alleles) in B. The skeletal PSI data is not available for 3 I-band exons with allele counts in NM cases or gnomAD controls; thus variants that we present here do not sum to 100%.
See this image and copyright information in PMC

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