Abstract Introduction ATTR-CM results from the accumulation of wild-type (wtATTR-CM) or mutated/variant (hATTR-CM) transthyretin in the heart. The differentiation between these two subtypes often supports the use of specific treatments and family counselling/screening. Our main goal was to assess the temporal trends of genetic testing in patients with ATTR-CM. Methods We performed a study enrolling consecutive patients with ATTR-CM since the inception of a dedicated rare disease primary cardiomyopathy program in our centre. The diagnosis of cardiac amyloidosis and the amyloid subtype was confirmed according to the algorithm of Gilmore and colleagues. Genetic testing for transthyretin variants was performed using next-generation sequencing from blood samples collected from each patient after written informed consent, as per site protocol. Further molecular confirmation of the variants was performed by standard Sanger sequencing. All transthyretin (TTR) variants are classified as per the American College of Medical Genetics and Genomics Guidelines. Results A total of 280 patients with confirmed ATTR-CM were included, which accounts for a mean of 47 new diagnosis per year (31, 12, 37, 66, 44 and 58 diagnoses in 2019, 2020, 2021, 2022, 2023 and 2024, respectively). Of these, 157 patients (56% of the cohort, age 81 ± 8 years, 75% male) performed genetic testing, of which 150 have received results. This corresponds to an average of 27 genetic tests requests per year. When analysed per year, 58%, 63%, 73%, 65%, 62% and 55% of the patients in the cohort in 2019, 2020, 2021, 2022, 2023 and 2024, respectively, were genetically tested. The absolute amount of genetic testing requests increased from the start of the program. Pathogenic variants in the TTR gene were found in 21 patients, median age 71 (67-75) years old at the time of diagnosis. Moreover, 3 individuals are followed as asymptomatic carriers detected through family screening. The most frequently identified mutations were the Val142Ile (14 patients) and Val50Met variants (10 patients). Compared with wtATTR-CM, patients with hATTR-CM were younger (median age 71 (IQR 67-75) vs. 83 (78-87) years; p 0.001). No significant differences were found in the prevalence of hATTR-CM in males vs. females and patients with vs. without extracardiac manifestations. Clinical presentation is summarized in Figure 1. Conclusion Over the last years, routine TTR genetic testing is becoming standard-of-care for patients with ATTR-CM. In our cohort, a positive causal gene variant was found 14% of the cases. The identification of hATTR-CM often promoted personalized approach with directed therapies and cascade family screening.
Amador et al. (Sat,) studied this question.