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. 2025 Apr 30:102419.
doi: 10.1016/j.jchf.2025.01.024. Online ahead of print.

The p.Asn271Ile Variant in the TNNT2 Gene Is Associated With Low-Risk Late-Onset Hypertrophic Cardiomyopathy

José M Larrañaga-Moreira  1 , Juan P Ochoa  2 , Rosalía Peteiro-Debén  3 , Esteban Martín-Álvarez  4 , Tomás Ripoll-Vera  5 , Jorge Álvarez-Rubio  5 , María L Peña-Peña  6 , Helena Llamas-Gómez  6 , Adrián Fernández  7 , María Gallego-Delgado  8 , Ana I Rodríguez-Serrano  9 , Carles Díez-López  10 , Perry M Elliott  11 , Julián Palomino-Doza  12 , Rebeca Lorca  13 , Javier Limeres  14 , Olga Azevedo  15 , Esther Zorio  16 , Ernesto Martín-Dorado  17 , Irene Méndez-Fernández  18 , Raúl Franco-Gutiérrez  19 , Fernando de Frutos  20 , Aida Escudero  21 , Luis Ruiz-Guerrero  22 , Alejandro Rodríguez-Vilela  23 , Andrea Mazzanti  24 , William J McKenna  25 , Roberto Barriales-Villa  26 ; TNN Investigators
Collaborators, Affiliations

The p.Asn271Ile Variant in the TNNT2 Gene Is Associated With Low-Risk Late-Onset Hypertrophic Cardiomyopathy

José M Larrañaga-Moreira et al. JACC Heart Fail. .

Abstract

Background: Variants in the cardiac troponin T gene (TNNT2) are a cause of hypertrophic cardiomyopathy (HCM) where mild TNNT2 structural phenotypes may be associated with sudden cardiac death.

Objectives: This study aims to demonstrate a founder effect in A Coruña (Spain) and characterize the phenotype of the TNNT2 p.Asn271Ile variant in comparison with codon 92 variants, a hotspot previously associated with high risk.

Methods: Probands and relatives carrying the TNNT2 p.Asn271Ile variant were retrospectively recruited from a multicenter registry. Haplotype analysis was performed in 18 unrelated probands. The primary endpoint was a composite of malignant ventricular arrhythmia and end-stage heart failure. Clinical characteristics, penetrance, and outcomes were compared with codon 92 variants' carriers (p.Arg92Trp/Gln/Pro).

Results: The TNNT2 p.Asn271Ile cohort comprised 159 individuals (46 probands) from families mainly from the A Coruña region (33 of 48). Haplotype analysis revealed a common ancestor around 650 years ago. Late-onset HCM and incomplete age-related penetrance were observed (estimated median diagnosis age 60.1 years). Men were diagnosed 18.4 years before women (P < 0.001). The phenotype was predominantly mild, with a median left ventricular thickness of 17 mm; only 4.2% of patients reached the primary endpoint (3.2% malignant ventricular arrhythmia, 1.1% end-stage heart failure). Codon 92 variants' carriers (76 individuals, 28 probands) had a higher penetrance, being diagnosed 19.4 years earlier, and they exhibited a significantly worse prognosis (primary endpoint in 34.3%; P < 0.001).

Conclusions: The p.Asn271Ile variant in the TNNT2 gene is associated with late onset HCM, with a low risk of adverse events. Variant-specific rather than gene-specific prognosis should be considered during sudden cardiac death risk assessment.

Keywords: TNNT2; haplotype; hypertrophic cardiomyopathy; penetrance; sudden death; troponin T.

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Conflict of interest statement

Funding Support and Author Disclosures This work has been supported by a grant from the Sociedade Galega de Cardioloxía (SOGACAR). The following centers are members of the European Reference Network for rare, low-prevalence, and complex diseases of the heart (http://www.guardheart.ern-net.eu): Barts Heart Centre, St Bartholomew’s Hospital, London; University Hospital Puerta de Hierro Majadahonda, Madrid, Spain; University Hospital Virgen Arrixaca, Murcia, Spain; IRCCS ICS Maugeri, Pavia, Italy; Gregorio Marañón General University Hospital, Madrid, Spain; Vall d’Hebron University Hospital, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain; and Virgen del Rocio University Hospital, Sevilla, Spain. Blood samples at Hospital Universitario y Politécnico La Fe were provided by the Biobanco La Fe (B.0000723), and they were processed following standard operating procedures with the appropriate approval of the Ethics and Scientific Committees. Drs Larrañaga and Limeres have received speaker fees and served on the advisory boards of BMS. Dr Barriales has received speaker fees and served on the advisory boards of BMS and Cytokinetics and has received grants from Healthincode. Dr Elliott has performed consultancies for Pfizer, Biomarin, Cytokinetics, and BMS; and has received unrestricted grants from Sarepta. Dr McKenna has served on the advisory boards of Health in Code and Tenaya Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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