TY - JOUR
T1 - Analysis of TTN Truncating Variants in >74 000 Cases Reveals New Clinically Relevant Gene Regions
AU - Vatta, Matteo
AU - Regalado, Ellen
AU - Parfenov, Michael
AU - Swartzlander, Dan
AU - Nagl, Andrea
AU - Mannello, Meghan
AU - Lewis, Rachel
AU - Clemens, Daniel
AU - Garcia, John
AU - Ellsworth, Rachel E.
AU - Morales, Ana
AU - Ting, Yi Lee
AU - Aradhya, Swaroop
N1 - Publisher Copyright:
© 2025 The Authors. Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc.
PY - 2025/4/1
Y1 - 2025/4/1
N2 - 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.
AB - 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.
KW - alleles
KW - arrhythmias, cardiac
KW - cardiomyopathies
KW - exons
KW - neuromuscular diseases
UR - http://www.scopus.com/inward/record.url?scp=105002458247&partnerID=8YFLogxK
U2 - 10.1161/CIRCGEN.124.004982
DO - 10.1161/CIRCGEN.124.004982
M3 - Article
C2 - 39968638
AN - SCOPUS:105002458247
SN - 2574-8300
VL - 18
SP - e004982
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
IS - 2
ER -