1 - Unidade de Genética Médica, Área de Pediatria, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central (CHULC), Lisboa, Portugal
2 - Centro de Genética Preditiva e Preventiva (CGPP), Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Portugal
3 - UnIGENe, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Portugal
4 - Departamento de Ciências Médicas, Universidade de Aveiro
5 - Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
*Last/senior authors
- 27.ª Reunião Anual da Sociedade Portuguesa de Genética Humana (SPGH), 23-25 novembro 2023, Lisboa – Portugal
- (Reunião nacional, publicação sob forma de resumo)
Introduction: The application of whole-exome sequencing (WES) for diagnostic purposes has the potential to unravel secondary findings unrelated with the primary purpose of the genetic test. These are of high clinical utility and comprise disease causing variants in genes related to life-threatening and/or preventable diseases. Clarifying the allelic frequencies of disease-causing variants in specific populations is a crucial step in implementing genomic medicine on a large scale. However, this data is currently unavailable for the Portuguese population.
Methodology: We analyzed medically actionable variants in 81 genes from the ACMG list (v3.2) of actionable loci using WES data obtained from a large laboratory cohort comprising 12,167 samples which was tentatively resampled to be representative of the Portuguese population (3,972 individuals).
Results: We identified a total of 643 (230 distinct) pathogenic (PAT) or likely pathogenic (L-PAT) variants across 49 ACMG genes, with an overall frequency of 8.1%. Cardiovascular diseases group was the most predominant with actionable results (2.6% of the individuals), being the most frequent PAT/L-PAT variants found in genes related to cardiomyopathies (TTN and MYH7), dyslipidemias (LDLR), heart conduction disorders (KCNQ1), and aortopathies (FBN1). The second represented group of disorders was cancer predisposition (1.7%) and included variants in genes related to colon cancer (PMS2, MSH6 and MSH2) and breast cancer susceptibility (BRCA2, PALB2, and BRCA1). Finally, we also observed actionable variants related with miscellaneous disorders (1.0%) and metabolic disorders (0.1%), such as hereditary transthyretin amyloidosis (TTR), malignant hyperthermia (RYR1), and the X-linked Fabry disease (GLA).
Discussion: Overall, our results suggest that medically actionable findings can be identified in approximately 5.4% of the Portuguese population. To the best of our knowledge, this is the first study estimating medically actionable findings in our country. These results provide valuable information for patients, practitioners, and stakeholders involved in genomic medicine. Ultimately, they may support the implementation of an organized genomic opportunistic screening program, tailored to improve healthcare in Portugal.
Palavras Chave: Whole Exome Sequencing (WES); actionable findings; Portuguese population