Hereditary Transthyretin-Related Amyloidosis Ongoing Observational Study: A Baseline Report of the First 3167 Participants

<b>Background</b>: Hereditary transthyretin-related amyloidosis is a clinically heterogeneous autosomal dominant disease caused by pathogenic variants in the <i>TTR</i> gene (hATTR amyloidosis). <b>Objective:</b> The current study describes the demographic, clinical, and genetic characteristics of patients with suspected hATTR amyloidosis. <b>Methods</b>: This study is part of the "Hereditary transthyretin-related amyloidosis and longitudinal monitoring of <i>TTR</i>-positive patients" (TRAMmoni<i>TTR</i>) study. This study included 3167 participants, along with their clinical details. Principal component (PC) analysis was used to analyze their clinical symptomatology. Next-generation sequencing of the <i>TTR</i> gene was performed and genotype-phenotype relationships were investigated. We compared the demographic and clinical characteristics using the principal components (PCs) and also compared participants with and without the <i>TTR</i> pathogenic variants. <b>Results:</b> We identified five main clinical phenotypes out of 22 single symptoms that explained 49% of the variation. The first two PCs referred to polyneuropathy and cardiomyopathy. We found significant differences between gender and PC-polyneuropathy and PC-cardiomyopathy, with male over-representation in the higher quantiles of PC-polyneuropathy and male under-representation in the lowest quantiles of PC-cardiomyopathy. We identified 92 participants with hATTR (3%), exhibiting 17 unique heterozygous <i>TTR</i> variants. The p.Val50Met variant was the most frequent. Furthermore, 503 participants (20%) were identified with ATTR and no relevant <i>TTR</i> variants (ATTRwt). We detected significant differences between the ATTRwt and hATTR groups, with male gender predominance in only the ATTRwt group and a positive family history of polyneuropathy and/or cardiomyopathy among the hATTR participants. <b>Conclusions</b>: The current clinical and genetic characterization of this cohort serves as a foundation for further longitudinal monitoring and assessment.