Abstract 13585: Genomics-first Evaluation of Phenotypes Associated With Pathogenic or Likely Pathogenic Transthyretin Variants

Abstract

Introduction: Hereditary transthyretin ( TTR ) amyloidosis as a cause of cardiomyopathy has historically been challenging to diagnose. With increased genetic testing, quantification of penetrance and disease associations through genomics-first approach provides a first step towards improved diagnosis and treatment. Methods: In the Geisinger MyCode Community Health Initiative, we identified pathogenic and likely pathogenic (P/LP) variants in TTR from 135,878 individuals with exome sequence data linked to electronic health records (DiscovEHR cohort) using ANNOVAR. We compared diagnoses and imaging findings between TTR variant carriers/noncarriers using SAIGE mixed linear models. Results: We observed 7 P/LP TTR variants (6 P, 1 LP) in 158 individuals (0.12%; 142 P, 16 LP). Median carrier age was 52 (IQR: 37-61) and 43% were male. The most common variant was V122I (i.e., p.V142I; 114, 0.08%). Most TTR variant carriers were of African ancestry (58%), all of whom carried V122I, consistent with the frequency of this variant in that population (2.6%). Observed associations with cardiac amyloidosis (odds ratio (OR): 2.8E 20 , p = 0.03) and non-specific amyloidosis (OR: 4E 4 , p = 0.03) were significant, although prevalence was low (n = 1 and 2 TTR carriers, respectively). No associations were observed with other specified diagnoses (Figure) or imaging findings. Considering only individuals aged ≥60, we observed a significant association with non-ischemic, non-dilated cardiomyopathy diagnoses (OR: 5.8, p=0.04) involving carriers of V122I (n = 3), V30M (p.V50M), T60A (p.T80A), and I68L (p.I88L; n = 1 each). Conclusion: Genomics-first screening of a clinical population for P/LP variants in TTR has a moderate to high yield depending on population ancestry. In the absence of symptoms or family history, initiating routine surveillance may be most appropriate after age 60. Deeper phenotyping is warranted to better characterize penetrance and ramifications for management.