Asymptomatic Individuals with Family History of Hereditary Transthyretin-Mediated Amyloidosis can be Detected almost Two Decades Earlier Than Symptomatic Probands

Introduction Hereditary transthyretin-mediated (hATTR) amyloidosis is an autosomal dominant disease characterized by extracellular deposition of amyloid fibrils composed of transthyretin (TTR) protein, with the majority of patients developing a mixed phenotype of polyneuropathy and cardiomyopathy. To facilitate earlier diagnosis, Alnylam Pharmaceuticals, Inc and Invitae have partnered to offer Alnylam Act®, a no-charge sponsored genetic testing and counseling program for individuals ≥18 years old with suspected diagnosis or a confirmed family history of hATTR amyloidosis. We sought to determine if reported family history and/or symptoms correlated to earlier detection of TTR variants in this cohort. Hypothesis We hypothesized that age at time of testing was earlier in individuals with a reported family history compared to probands with reported symptoms and no family history. Methods From April 2017 to March 2020, 21,235 unrelated individuals were tested for TTR variants in a CLIA-certified laboratory. We analyzed three groups: (1) probands with reported symptoms and positive family history, (2) probands with reported symptoms without family history, and (3) asymptomatic individuals with family history of hATTR amyloidosis. Family members who were also tested through the program were excluded from analysis. Results The overall yield of positive TTR genetic tests in symptomatic probands with no reported family history was 778/20134 (3.9%), which was lower compared to those with reported family history (symptomatic 26.7%; asymptomatic 31.5%; Table 1). Among 778 symptomatic probands with no reported family history and positive TTR results, mean age at testing was 70.5 years. In contrast, those with family history were tested at an earlier age (symptomatic 59.3 years, p Conclusions Mean age at testing of TTR positive asymptomatic individuals with a reported familyhistory of hATTR amyloidosis is lower than TTR positive symptomatic probands without a family history by almost two decades, with an 8-fold higher yield (OR 11.4, 95% CI: 9.5-13.8). Here, we demonstrate knowledge of family history alone is a powerful predictor of the presence of TTR variants, emphasizing the importance of family testing once a confirmed case is identified, which may facilitate earlier diagnosis.