Spectrum and Clinical Interpretation of TTN Variants in Ecuadorian Patients with Heart Disease: Insights into VUS and Likely Pathogenic Variants
Journal
International Journal of Molecular Sciences
ISSN
1422-0067
Date Issued
2025-12-10
Author(s)
Rita Ibarra Castillo
José Luis Laso-Bayas
Abstract
This study described TTN gene variants in Ecuadorian patients with hereditary cardiac diseases, integrating genetic ancestry to improve variant interpretation in an underrepresented population.
Sixty patients with confirmed hereditary cardiac conditions were analyzed using the TruSight Cardio NGS panel (Illumina, San Diego, CA, USA), which targets 174 cardiac-associated genes.
Bioinformatic analyses and classification were performed in accordance with ACMG/AMP guidelines, and ancestry inference was conducted using 46 Ancestry Informative Markers (AIM-InDels). From 4008 detected TTN variants, 29 variants of interest remained after filtering: 27 classified as variants of uncertain significance (VUS) and two as likely pathogenic. All variants were heterozygous and distributed across exons 3–358, primarily in the A-band region, commonly associated with cardiomyopathies and arrhythmic phenotypes.
Two truncating variants (exons 267 and 272) met PVS1 criteria, while several missense variants (p.Ser91Gly, p.Pro12140Ser, p.Arg34653Cys) showed possible modulatory effects on hypertrophic or arrhythmic outcomes. Genetic ancestry revealed a predominant Native American background, followed by European and African components.
These findings expand the understanding of TTN-related cardiac disease in Latin America, suggesting that TTN functions as a genetic modifier influencing disease expression. Incorporating ancestry information enhances genomic interpretation and supports precision medicine in diverse populations.
Sixty patients with confirmed hereditary cardiac conditions were analyzed using the TruSight Cardio NGS panel (Illumina, San Diego, CA, USA), which targets 174 cardiac-associated genes.
Bioinformatic analyses and classification were performed in accordance with ACMG/AMP guidelines, and ancestry inference was conducted using 46 Ancestry Informative Markers (AIM-InDels). From 4008 detected TTN variants, 29 variants of interest remained after filtering: 27 classified as variants of uncertain significance (VUS) and two as likely pathogenic. All variants were heterozygous and distributed across exons 3–358, primarily in the A-band region, commonly associated with cardiomyopathies and arrhythmic phenotypes.
Two truncating variants (exons 267 and 272) met PVS1 criteria, while several missense variants (p.Ser91Gly, p.Pro12140Ser, p.Arg34653Cys) showed possible modulatory effects on hypertrophic or arrhythmic outcomes. Genetic ancestry revealed a predominant Native American background, followed by European and African components.
These findings expand the understanding of TTN-related cardiac disease in Latin America, suggesting that TTN functions as a genetic modifier influencing disease expression. Incorporating ancestry information enhances genomic interpretation and supports precision medicine in diverse populations.