Genotypic And Phenotypic Differences And Similarities Among Patients With Inherited Cardiovascular Diseases: Insights From A Genetic Testing Program

Introduction Hereditary transthyretin amyloidosis (hATTR/ATTRv) is a progressive, and fatal disease caused by mutations in the transthyretin gene (TTR). These mutations destabilize protein folding, resulting in amyloid deposits and causing multisystem dysfunction such as cardiomyopathy (CM), whose etiology may be attributed to traditional causes of cardiovascular diseases (CVDs). Genetic testing was recently added to the diagnostic armamentarium for ATTR CM. Hypothesis A molecular diagnostic program will help improve differential diagnosis and describe prevalence and characteristics of patients with TTR mutations versus patients with mutations associated with other inherited CV conditions. Methods Data from patients enrolled in the hATTR Compass Program, which provides confidential genetic testing to patients in the US, Canada, and Puerto Rico with possible hATTR with polyneuropathy or with a family history of hATTR, were analyzed. DNA next-generation sequencing was performed using a panel of 92 genes associated with inherited CV conditions. Results A total of 978 patients under the care of cardiologists were referred for testing using this panel; 74 patients were positive for TTR mutations and 52 were positive for other non-TTR CV pathogenic mutations. The most common TTR mutation was p.V142I (V122I). Most patients (66.2%) with a TTR mutation did not have a family history of hATTR. Of patients with non-TTR mutations, 16 had mutations in the MYBPC3 locus, associated with CM. Patients with TTR mutations were older than those with non-TTR mutations (mean age, 67 vs 53 years). Both groups had similar proportions of heart disease (89% TTR vs 90% other CVD). Some key indicators of hATTR were more prevalent in patients with non-TTR versus TTR mutations: autonomic (21% vs 14%), motor (19% vs 12%), and gastrointestinal dysfunction (17% vs 8%, respectively); however, bilateral carpal tunnel syndrome (0% vs 26%) and sensory dysfunction (15% vs 28%) were more prevalent in patients with a TTR mutation. More patients with TTR mutations had other diagnostic tests (eg, PYP imaging, biopsy) than those with non-TTR mutations (34% vs 15%). A limitation of this analysis was that symptoms may have been underreported because of the simplified, voluntary nature of participation and data collection. Conclusion Despite newer imaging methods such as PYP imaging, hATTR is commonly undiagnosed. Because hATTR can progress rapidly, it is imperative that an accurate diagnosis be made early to institute appropriate therapy; genetic testing is key for obtaining an accurate diagnosis.