Phenotypic presentation of family members of ATTRv probands and subsequent disease penetrance

Abstract

BACKGROUND: Hereditary transthyretin amyloid cardiomyopathy (ATTRv-CM) is being increasingly diagnosed due to enhanced awareness and availability of newer therapeutics. Multiple TTR variants have been described worldwide, but with uncertain disease penetrance. The characteristics and outcomes of "previously undiagnosed" pathogenic-likely pathogenic (P/LP) TTR variant (genotype or G+; cardiac phenotype or P-) carriers are unknown which has important prognostic and therapeutic implications, especially for affected family members. This descriptive study aimed to delineate phenotype and cardiac penetrance in "previously undiagnosed" G+P- family members of ATTRv probands. METHODS: Demographic, electrocardiographic (ECG), genetic, and imaging (echocardiography, cardiac technetium-99m pyrophosphate (PYP) and magnetic resonance imaging) data were analyzed. The prediction effect of selected baseline characteristics for ATTRv-CM development was evaluated. Kaplan-Meier and Cox regression methods were used to describe risk and predictors of ATTRv-CM development in family members. RESULTS: There were 85 G+P- family members identified. Mean age was 48.5±11.7 years, 39% were male, 18% had a diagnosis of peripheral neuropathy, 15% with a history of carpal tunnel syndrome, and 4% had atrioventricular block at baseline. Of these, 55 patients had follow-up imaging studies. After a median 6.8-year follow-up, 22% developed ATTR-CM with a 10-year estimated risk of 29.5% (95% CI 7.9-46.0). Cardiac penetrance increased with increasing family member's age. Proband's diagnosis age (p=0.0096) and artificial intelligence (AI)-ECG prediction (p=0.0091) were promising baseline predictors of time to ATTRv-CM development. CONCLUSION: In previously undiagnosed G+P- ATTRv family members, the incidence of subsequent CM is high. Predictors for CM development such as proband's diagnosis age and AI-determined ECG probability of ATTR-CM require further investigation.