Unrelated Individuals of Self-Reported White/Caucasian Ancestry with the P.Val142Ile (V122I) Variant of Hereditary Transthyretin-Mediated Amyloidosis are Phenotypically Similar to those with Self-Reported Black/African-American Ancestry

Abstract

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. The most common variant in the United States is p.Val142Ile (V122I) with a prevalence of 3-4%, most commonly observed in the Black/African-American population. 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 of hATTR amyloidosis or a confirmed family history of hATTR amyloidosis. A novel cohort of self-reported White/Caucasian unrelated individuals with the p.Val142Ile (V122I) variant has been identified by this program. Methods Between April 2017 and March 2020, 21,235 unrelated individuals were tested for TTR variants in a CLIA-certified laboratory. We analyzed all unrelated individuals with the p.Val142Ile (V122I) variant discovered through the Alnylam Act® program, including all reported demographic (e.g., age, ancestry) and symptomatic characteristics available. Results In total, we observed 795 unrelated individuals with the p.Val142Ile (V122I) variant. We identified 29 unrelated individuals of White/Caucasian ancestry and who carry the p.Val142Ile (V122I) variant, which represents 11.4% of the 254 unrelated White/Caucasian individuals with a TTR positive variant found within the Alnylam Act® program to date. The reported symptoms in these individuals are similar to the Black/African-American p.Val142Ile (V122I) population in this cohort (Figure). Conclusions A novel cohort of White/Caucasian unrelated individuals with the p.Val142Ile (V122I) TTR variant has been identified with similar reported clinical features compared to those with Black/African-American ancestry and the same variant. This is the largest single cohort of individuals of White/Caucasian ancestry with the p.Val142Ile (V122I) variant to be reported thus far, demonstrating the importance of TTR testing in individuals with symptoms of hATTR amyloidosis regardless of self-reported ancestry.