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

Purpose Secondary 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.

This study aimed to outline the profile of SF in the Brazilian Rare Genomes Project (BRGP).

We analyzed retrospectively SF (ACMG) data from GS of 5,402 BRGP individuals.

Of 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.

SF 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. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was funded by Hospital Israelita Albert Einstein in partnership with PROADI-SUS from the Brazilian Ministry of Health (Law 12.101/2009). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Hospital Israelita Albert Einstein gave ethical approval for The Brazilian Rare Genomes Project and related studies (CAAE: 9567220.4.1001.0071). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Avaliability The anonymized data supporting the findings of this study are provided in Table 1 in supplementary material. Further details regarding the data and variants can be obtained upon request from the corresponding author.