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