Section 1 of 5
Introduction
Francesco Cappelli, Carlo Fumagalli, Marco Luigetti, Roberta Mussinelli, Simone Longhi, Pietro Guaraldi, Alberto Aimo, Alessia Argirò, Alessandro Barilaro, Elena Biagini, Giulia Biagioni, Marco Ceccanti, Alberto Cipriani, Cristina Chimenti, Laura De Michieli, Gianluca Di Bella, Michele Emdin, Francesca Graziani, Massimo Imazio, Giuseppe Limongelli, Carla Lofiego, Francesco Musca, Paolo Ossola, Mario Nuvolone, Stefano Perlini, Maurizio Pieroni, Aldostefano Porcari, Beatrice Musumeci, Giuseppe Palmiero, Federico Perfetto, Irene Ruotolo, Massimo Russo, Giacomo Tini, Giuseppe Vergaro, Fabio Vagnarelli, Federica Verrillo, Maria Ausilia Sciarrone, Alessandro Salvalaggio, Mattia Zampieri, Carlotta Mazzoni, Gianfranco Sinagra, Giovanni Palladini, Marco Merlo, and Laura Obici · about 1 minutes
Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant disease caused by genetic defects of the transthyretin gene (TTR) causing misfolding of the transthyretin (TTR) protein, resulting in amyloid fibril deposition, primarily (but not exclusively) in the heart and peripheral nerves.1 Disease expression varies by mutation, ranging from prevalent sensorimotor polyneuropathy with autonomic dysfunction to predominant cardiomyopathy, and often consists of a mixed phenotype.2
Cascade genetic testing has been adopted in other hereditary cardiovascular conditions, demonstrating beneficial effects for at-risk family members allowing early and tailored management.3,4 With the recent introduction of disease-specific drugs, it has been proposed that in ATTRv, early identification through family screening can improve outcomes by facilitating timely interventions.5 Indeed, detecting presymptomatic or mildly symptomatic individuals could potentially provide the opportunity to initiate disease-modifying treatments before irreversible organ damage occurs.
The penetrance of ATTRv is not fully understood,6–8 and while screening is recommended approximately 10 years before the predicted age of disease onset (PADO) according to mutation and family history,9,10 the rate and age of conversion may vary widely by gender, ethnicity, and other unknown factors.6 As the Italian universal healthcare system provides comprehensive coverage for presymptomatic genetic testing, monitoring, and treatment, Italy represents an ideal setting to test the clinical impact of cascade genetic screening in ATTRv, also considering the presence of several referral centres, and the prevalence of different pathogenic genetic variants across the country. In addition, cascade genetic screening is generally well accepted by patients and their relatives, as the Italian laws ensure strict regulation of genetic information and privacy.11
With the present study, we aimed to describe the diagnostic and prognostic impact of cascade genetic testing for ATTRv, focusing on prevalence of the disease among screened family members, variant conversion rates, and on long-term outcomes.