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

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.

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.

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).

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).

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.