Cascade genetic screening in families with hereditary transthyretin amyloidosis: diagnostic and prognostic impact

Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant disease with variable penetrance. Cascade genetic screening may enable earlier diagnosis and intervention, but its prognostic impact remains unclear.

This study retrospectively analysed 967 individuals from 431 families between 2004 and 2024 across 15 Italian referral centres. Participants were categorized as ATTRv index cases, symptomatic carriers (genotype-positive/phenotype-positive [G+/P+]), or asymptomatic carriers (genotype-positive/phenotype-negative [G+/P-]). Clinical characteristics, disease conversion, and survival were evaluated.

Following identification of 398 index cases, genetic screening of 1243 relatives identified 569 carriers (461 G+/P-, 108 G+/P+). Among the 461 G+/P-, over a median follow-up of 5.3 [1.7-9.8] years, 77 (16.7%) patients developed a clinical diagnosis of ATTRv: Glu89Gln (42.2%, 95% confidence interval [CI] 28.8-56.9), Phe64Leu (24.7%, 95% CI 16.1-35.8), Val30Met (13.1%, 95% CI 7.4-22.1), Ile68Leu (7.3%, 95% CI 4.1-12.8), and Val122Ile (5.1%, 95% CI 1.3-18.3), other variants 22.9% (95% CI 14.5-34.1). Notably, 11/62 (17.7%) carriers converted >10 years earlier than the predicted age of disease onset. G + P+ patients had better survival than index (hazard ratio [HR] 0.43, 95% CI 0.24-0.79), and mixed phenotype showed worse outcomes than cardiac presentations. Disease-modifying therapy was independently associated with lower mortality (HR 0.11, 95% CI 0.01-0.17).

Cascade genetic screening facilitated earlier diagnosis and was associated with improved survival, likely related to identification at an earlier stage of disease and timely treatment initiation. Variant-specific follow-up is essential, as some carriers convert earlier than predicted. Systematic, genotype-informed surveillance in ATTRv is key to optimize outcomes.