P007. Genotypic and Phenotypic Differences and Similarities Among Patients With Transthyretin Amyloidosis or Other Inherited Cardiovascular Diseases: Insights From a Genetic Testing Program

Background Hereditary transthyretin amyloidosis (hATTR or ATTRv [variant]) is a progressive, and fatal disease caused by mutations in the transthyretin (TTR) gene. These mutations destabilize protein folding, resulting in amyloid deposits and causing multisystem dysfunction such as cardiomyopathy, whose etiology may be attributed to traditional causes of cardiovascular diseases. Genetic testing was recently added to the diagnostic armamentarium for ATTR with cardiomyopathy. Heart failure nurses, whether registered nurses or advanced practice nurses, can have a pivotal role in appropriately diagnosing hATTR as the underlying cause of heart failure. Objective 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 cardiovascular conditions. Methods Data from patients enrolled in the hATTR Compass program, which provides confidential genetic testing to patients in the United States (including Puerto Rico) and Canada 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 cardiovascular 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 cardiovascular 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 cardiomyopathy. 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 cardiovascular diseases). 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 TTR mutations. A limitation of this analysis was that symptoms may have been underreported because of the simplified, voluntary nature of participation and data collection. More patients with TTR mutations had other diagnostic tests (eg, pyrophosphate imaging, biopsy) than those with non-TTR mutations (34% vs 15%). Conclusion Despite newer diagnostic methods such as pyrophosphate imaging, hATTR is commonly undiagnosed. Because hATTR can progress rapidly and be fatal, it is imperative that an accurate diagnosis be made early to institute appropriate therapy; genetic testing is key for obtaining an accurate diagnosis. Heart failure nurses are uniquely positioned to recognize the multiple symptoms that should raise clinical suspicion and help in the early diagnosis of hATTR.