Genetic landscape of hereditary transthyretin amyloidosis in Spain: a multicentric retrospective study

Hereditary transthyretin amyloidosis (ATTRv) is a rare, progressive disorder caused by TTR gene variants, leading to amyloid fibril deposition and clinical manifestations like cardiomyopathy and polyneuropathy. National data for Spain are scarce, despite known high-prevalence areas such as Majorca.

This multicentric, retrospective study analysed 4,526 individuals from 48/52 Spanish regions between 2015 and 2024, including 3,960 index cases and 566 at-risk relatives. Genetic testing was performed to identify pathogenic TTR variants.

Among 393 carriers of pathogenic variants, the most prevalent were p.Val50Met (64.1%) and p.Val142Ile (29.5%). Regional prevalence varied, with new high-prevalence areas identified, including Cádiz, Castellón, Ciudad Real, Huelva, Valencia and Zamora. A novel variant of unknown clinical significance, p.Ser137Thr, was found in two unrelated cases. Genotype-phenotype correlations showed p.Val50Met is linked to neurological phenotypes, while p.Val142Ile is associated with cardiac manifestations. A male predominance was observed in index cases, while the sex ratio in carrier relatives was similar to the general population.

This is the largest nationwide study of ATTRv in Spain, providing key insights into its genetic landscape. The findings suggest migratory factors may influence variant distribution, emphasising the importance of genetic screening for early diagnosis and management.