Background and aims: 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. Methods: 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. Results: 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). Conclusions: 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.
Cascade genetic screening in families with hereditary transthyretin amyloidosis: diagnostic and prognostic impact / Cappelli, Francesco; Fumagalli, Carlo; Luigetti, Marco; Mussinelli, Roberta; Longhi, Simone; Guaraldi, Pietro; Aimo, Alberto; Argirò, Alessia; Barilaro, Alessandro; Biagini, Elena; Biagioni, Giulia; Ceccanti, Marco; Cipriani, Alberto; Chimenti, Cristina; De Michieli, Laura; Di Bella, Gianluca; Emdin, Michele; Graziani, Francesca; Imazio, Massimo; Limongelli, Giuseppe; Lofiego, Carla; Musca, Francesco; Ossola, Paolo; Nuvolone, Mario; Perlini, Stefano; Pieroni, Maurizio; Porcari, Aldostefano; Musumeci, Beatrice; Palmiero, Giuseppe; Perfetto, Federico; Ruotolo, Irene; Russo, Massimo; Tini, Giacomo; Vergaro, Giuseppe; Vagnarelli, Fabio; Verrillo, Federica; Sciarrone, Maria Ausilia; Salvalaggio, Alessandro; Zampieri, Mattia; Mazzoni, Carlotta; Sinagra, Gianfranco; Palladini, Giovanni; Merlo, Marco; Obici, Laura. - In: EUROPEAN HEART JOURNAL. - ISSN 1522-9645. - (2026). [10.1093/eurheartj/ehag222]
Cascade genetic screening in families with hereditary transthyretin amyloidosis: diagnostic and prognostic impact
Ceccanti, Marco;Chimenti, Cristina;Musumeci, Beatrice;Tini, Giacomo;
2026
Abstract
Background and aims: 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. Methods: 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. Results: 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). Conclusions: 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
