P345: Nine categories of pitfalls in initial genetic testing for rare disorders reporting inappropriate negative, inconclusive or positive results

HF death.Analysis was stratified by underrepresented group status and by genotype.Patients with a variant classified as pathogenic or likely pathogenic were considered genotype (+), while those with a Variant of Uncertain Significance (VUS), benign or likely benign variant, or no variants detected were classified as genotype (-).Data analysis was performed using STATA.Results: There were 365 total patients included in the analysis, 225 UR patients and 140 NHW patients.There was no difference in genotype positivity between UR patients and NHW patients (genotype (+): UR = 17.3%, NHW = 17.9%).Genotype (+) UR patients had the youngest mean age at diagnosis (45.2 years), followed by genotype (-) UR patients (48.3 years), then genotype (-) NHW patients (55.3 years), and genotype (+) NHW patients (58.6 years) (p <0.001).Genotype (+) patients experienced more HF events overall than genotype (-) patients (39.1% vs 23.3%, p = 0.009).When stratified by underrepresented status, genotype (+) UR patients had the highest rate of HF events (41.0%), followed by genotype (+) NHW patients (36.0%), genotype (-) UR patients (26.3%), and lastly genotype (-) NHW patients (18.3%) (p = 0.024).Genotype (+) patients had worse outcomes than genotype (-) patients in time-to-event analysis regardless of UR status (median age: 68.9 vs 74.7, p = 0.029).When patients were stratified by UR status in the absence of genetic data, UR patients had worse HF outcomes in time-to-event analysis (p = <0.001).In timeto-event analysis, genotype (+) UR patients had the worst overall outcomes (median age = 63 years), followed by genotype (-) UR patients (median age = 69 years), and subsequently genotype (+) NHW patients (median age = 72.4) and lastly genotype (-) NHW patients.Conclusion: In patients with NiCM, underrepresented status and genotype positivity are associated with increased HF outcomes.In both NHW and UR populations, genotype positivity is associated with worse outcomes, consistent with previous literature.Analysis stratifying by underrepresented status and genotype suggests higher severity of disease in UR patients when compared to NHW patients.Genotype (+) UR patients have a higher burden of HF events and have earlier HF events in time-to-event analysis than any other group, including genotype (+) NHW patients.Further research is needed to understand if this increased risk is due to uncharacterized genetic risk, which includes polygenic and epigenetic risk.