ACMG Secondary Findings in the Brazilian Rare Genomes Project: Insights from 5,402 genome sequencing

Abstract

PurposeSecondary findings (SF) are pathogenic or likely pathogenic variants in genes unrelated to the primary purpose of genetic testing. The American College of Medical Genetics (ACMG) provides guidelines on which SF should be reported, involving 81 genes linked to different conditions. With the increasing use of genome sequencing (GS), SF are more frequently detected, presenting challenges for healthcare systems. The Brazilian population is often underrepresented in genomic studies, which limits population-specific knowledge. ObjectiveThis study aimed to outline the profile of SF in the Brazilian Rare Genomes Project (BRGP). MethodsWe analyzed retrospectively SF (ACMG) data from GS of 5,402 BRGP individuals. ResultsOf the 5,316 cases who consented to receive SF, 3.6% (191 cases) had at least one SF. The most common genes identified were TTR, TTN, and BRCA2. SF were mainly related to cardiovascular conditions (40.2%) and cancer predisposition (37.6%). Some variants, such as TTR: c.424G>A; p. (Val142Ile) and TP53: c.1010G>A; p. (Arg337His), were recurrent, reflecting population-specific traits and founder effects. Novel variants were 10.6% of SF. ConclusionSF rate varies across studies and populations. While SF can aid early diagnosis, their relevance is debated due to potential psychological and healthcare burdens. Effective genetic counseling and public health policies are essential.