Transthyretin gene variants in a population-based study of 9,957 Finnish men and in 366 Finnish patients with hypertrophic cardiomyopathy

Background Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) typically manifests after the age of 50 years with heart failure and high mortality. While wild-type disease (ATTRwt-CM) is more common, transthyretin variant amyloid cardiomyopathy (ATTRv-CM) is a rare, autosomal dominant disorder caused by pathogenic variants in the TTR gene. The Finnish population exhibits a unique genetic heritage shaped by historical genetic bottlenecks and isolation. Most of the ATTR-CM patients reported in Finland have ATTRwt-CM. Furthermore, in our previous nationwide FinHCM Study including 382 unrelated Finnish patients with hypertrophic CM (HCM), no pathogenic TTR variants were detected using a panel of 59 CM related genes, including TTR. Consequently, the prevalence of pathogenic TTR variants in Finns is assumed to be low, but there are no studies on the prevalence of TTR variants in the general native Finnish population. Methods TTR variants were investigated from whole-exome sequencing data of the population-based Metabolic Syndrome in Men (METSIM) Study including 9,957 Finnish men from Eastern Finland, aged 57.6±7.1 (45–74) years at baseline in 2005–2010. Additionally, TTR gene variants were re-investigated in 366 Finnish patients with HCM in the FinHCM Study, aged 53±14 (16–85) years at baseline in 1994–2010, using Sanger sequencing. Variants were classified according to the ACMG criteria. Clinical data of carriers with variants of uncertain significance (VUS) were collected from the FinHCM Study database and the medical records of the Kuopio University Hospital at the end of year 2025. Results A total of 26 TTR variants were identified: 23 in the METSIM Study and seven in the FinHCM Study. Seven variants (4 missense and 3 synonymous) located in exons, 15 in introns, three in the 5′ untranslated region (UTR), and one in a splice-site intron. Twenty-one variants were rare. No pathogenic or likely pathogenic variants were detected, including the variants reported in other populations, such as p.Val142Ile and p.Val50Met. Eight variants, including five novel, were classified as VUS (2 5′UTR and 6 intronic variants), while others were benign. In the METSIM Study cohort, nine men (0.09%) carried six different VUSs, while in the FinHCM Study, three patients (0.8%) carried two VUSs. Of the VUS carriers in the METSIM Study, one subject with the 5′UTR ­­-107G>A variant had CM with fatal heart failure, another had suspected biceps tendon rupture, and the intronic c.337-77C>T variant carrier had spinal stenosis, all characteristic of ATTR. Conclusions Pathogenic TTR variants were absent in both the large Finnish cohort of males and in Finnish HCM patients. However, carriers of one 5′UTR variant and one intronic VUS displayed clinical features characteristic of ATTR. Our study suggests a very low prevalence of hereditary ATTR in Finland and highlights the need for further investigation of the pathogenicity of non-coding TTR variants.