Genetic testing in patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM): high diagnostic yield in patients presenting with Heart Failure
M Vicente Soares, M Ramos, R Amador, R Gomes, D Correia, T Laranjeira, C Aguiar, S Maltes, B RochaAbstract
Introduction
Cardiac Amyloidosis (ATTR-CM) results from the deposition of wild-type (wtATTR-CM) or mutated/variant (hATTR-CM) transthyretin in the myocardium. Differentiating these subtypes is essential to guide targeted therapies, genetic counse ling and family screening.
Aims
To evaluate the temporal trends of genetic testing and the diagnostic yield in patients diagnosed with ATTR-CM.
Methods
Single-center retrospective study including consecutive patients with ATTR-CM fo lowed in a dedicated cardiomyopathy unit care, up to November 2025. Diagnosis of cardiac amyloidosis folowed the recommended multi-step algorithm. Genetic testing for transthyretin variants was performed using next-generation sequencing (NGS), with confirmation by Sanger sequencing. A l transthyretin (TTR) variants were classified according to ACMG guidelines.
Results
A total of 304 patients with confirmed ATTR-CM were included, corresponding to a mean of 43 diagnoses per year (33 in 2019, 14 in 2020, 42 in 2021, 72 in 2022, 53 in 2023, 59 in 2024 and 31 in 2025). Of these, 196 patients (64%) underwent genetic testing (mean age of 82 ± 7 years, 80% male), corresponding to an average of 28 test requests per year. When analyzed per year, 15%, 43%, 39%, 43%, 43%, 59% and 64% of the cohort in 2019 to 2025, respectively, were geneticaly tested. The number of tests increased steadily from the start of the program (5 in 2019; 15 in both 2020 and 2021; 34 in 2022; 23 in 2023; 70 in 2024; 36 in 2025 – with 25 additional ongoing tests). Pathogenic TTR variants were identified in 21 patients (11%). These patients presented with a mean age of 73 ± 7 years (range 41–93). The most frequently identified variant was Val142Ile (n=13), fo lowed by Val50Met (n=8). Compared with wtATTR-CM, those with hATTR-CM were significantly younger (73 ± 7 vs. 81 ± 6 years; p < 0.001). No significant differences were noted in cardiac disease severity at baseline. Most hATTR-CM patients presented firstly with cardiovascular manifestations, mainly heart failure (HF) (76%, n=16). Additionally, two patients presented with atrial fibrillation and other two with severe bradycardia requiring pacing. Extra-cardiac features varied by genotype: there was a higher burden of peripheral polyneuropathy in Val50Met carriers, whereas Val142Ile carriers generally showed minimal or mild extra-cardiac manifestations, with occasional subtle features (e.g., bilateral carpal tunnel syndrome).
Conclusion
Genetic testing has progressively become part of the standard of care in ATTR-CM. We found a diagnostic yield of 11% in ATTR-CM population presenting primarily with HF. Our study supports the standardization of routine genetic testing, as the identification of hATTR-CM has direct implications for targeted therapies, cascade screening and follow-up of relativesFor image description, please refer to the figure legend and surrounding text.