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. 2025 Apr 9;26(8):3509.
doi: 10.3390/ijms26083509.

Medically Actionable Secondary Findings from Whole-Exome Sequencing (WES) Data in a Sample of 3972 Individuals

Mafalda Melo  1 , Mariana Ribeiro  2   3 , Paulo Filipe Silva  2   3 , Susana Valente  2   3 , Filipe Alves  2   3 , Margarida Venâncio  1 , Jorge Sequeiros  2   3   4   5 , João Parente Freixo  2   3 , Diana Antunes  1   6 , Jorge Oliveira  2   3   4   5
Affiliations

Medically Actionable Secondary Findings from Whole-Exome Sequencing (WES) Data in a Sample of 3972 Individuals

Mafalda Melo et al. Int J Mol Sci. .

Abstract

The application of whole-exome sequencing (WES) for diagnostic purposes has the potential to unravel secondary findings unrelated with the primary reason of testing. Some of those might be of high clinical utility and comprise disease-causing variants in genes, related to life-threatening and clinically actionable diseases. Clarifying the allelic frequencies of such variants in specific populations is a crucial step for the large-scale deployment of genomic medicine. We analysed medically relevant variants in the 81 genes from the American College of Medical Genetics and Genomics (ACMG) v3.2 list of actionable loci, using WES data from a diagnostic laboratory cohort of 3972 persons, tentatively resampled to represent the Portuguese population geographic distribution. We identified medically actionable variants in 6.2% of our cohort, distributed across several disease domains: cardiovascular disorders (3.0%), cancer predisposition (2.0%), miscellaneous disorders (1.1%), and metabolic disorders (0.1%). Additionally, we estimated a frequency of heterozygotes for recessive disease alleles of 11.1%. Overall, our results suggest that medically actionable findings can be identified in approximately 6.2% of persons from our population. This is the first study estimating medically actionable findings in Portugal. These results provide valuable insight for patients, healthcare providers, and policymakers involved in advancing genomic medicine at the national and international level.

Keywords: actionable secondary findings; genomic medicine; whole-exome sequencing.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Flowchart of the variant filtering and curation process. RD: read depth; GQ: genotype quality; MAF: minor allele frequency of global population; PAT: pathogenic; L-PAT: likely pathogenic; BEN: benign; L-BEN: likely benign. * Variant impact according to Variant Effect Predictor (VEP) based on Sequence Ontology terms.
Figure 2
Figure 2
Total medically actionable findings and non-medically actionable findings (carrier status) present in our cohort of 3972 persons, presumed to be representative of the Portuguese population.
See this image and copyright information in PMC

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