Unveiling the Landscape of Reportable Genetic Secondary Findings in the Spanish Population: A Comprehensive Analysis Using the Collaborative Spanish Variant Server Database

ABSTRACT The escalating adoption of Next Generation Sequencing (NGS) in clinical diagnostics reveals genetic variations, termed secondary findings (SFs), with health implications beyond primary diagnoses. The Collaborative Spanish Variant Server (CSVS), a crowdsourced database, contains genomic data from more than 2100 unrelated Spanish individuals. Following the American College of Medical genetics (ACMG) guidelines, CSVS was analyzed, identifying pathogenic or likely pathogenic variants in 78 actionable genes (ACMG list v3.1) to ascertain SF prevalence in the Spanish population. Among 1129 samples, 60 reportable SFs were found in 5% of individuals, impacting 32 ACMG-listed genes, notably associated with cardiovascular disease (59.4%), cancer (25%), inborn errors of metabolism (6.3%), and other miscellaneous phenotypes (9.4%). The study emphasizes utilizing dynamic population databases for periodic SF assessment, aligning with evolving ACMG recommendations. These findings illuminate the prevalence of significant genetic variants, enriching understanding of secondary findings in the Spanish population. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work is supported by Postdoctoral Grant RH-0052-2021 of Rosario Carmona from Junta de Andalucia (Consejeria de Salud y Familias), co-funded by the European Union, European Social Fund (FSE) 2014-2020, and also by grants PID2020-117979RB-I00 from the Spanish Ministry of Science and Innovation and ER22P1AC715, ACCI 28 from CIBERER, ISCIII. The authors also acknowledge Junta de Andalucia for the postdoctoral contract of Carlos Loucera (PAIDI2020-DOC-00350) co-funded by the European Social Fund (FSE) 2014-2020. 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: Part of the dataset analyzed during the current study are available in the European Genome Archive (EGA) repository, https://www.ebi.ac.uk/ega/datasets/EGAD00001003101. The rest of data can be queried in the Collaborative Spanish Variant Server (CSVS) http://csvs.babelomics.org/. Aggregated data can be requested in CSVS (see downloads section) 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 Availability Part of the dataset analyzed during the current study are available in the European Genome Archive (EGA) repository, https://www.ebi.ac.uk/ega/datasets/EGAD00001003101. The rest of data can be queried in the Collaborative Spanish Variant Server (CSVS) http://csvs.babelomics.org/. Aggregated data can be requested in CSVS (see downloads section) List of abbreviations - ACGM - American College of Medical Genetics - CES - Clinical Exome Sequencing - CNV - copy number variants - CSVS - Collaborative Spanish Variant Server - SF - Secondary finding - WES - Whole Exome Sequencing - WGS - Whole Genome Sequencing