Frequency and spectrum of actionable secondary findings in the Maltese population

Abstract

Background: The identification of actionable secondary findings (SFs) through clinical exome sequencing has become increasingly relevant with the integration of genomics into routine healthcare. The frequency and spectrum of these findings vary across populations.

Methods: We analyzed exome sequencing data from 350 unrelated Maltese individuals, comprising 320 pseudonymised controls and 30 participants from the pilot sequencing phase of the national biobank DwarnaBio, to assess the prevalence of pathogenic or likely pathogenic (P/LP) variants in the ACMG SF v3.2 gene list. All samples underwent uniform sequencing, rigorous quality control, and variant interpretation according to ACMG/AMP guidelines.

Results: Actionable P/LP variants were identified in 12 individuals (3.4%) across autosomal dominant genes, predominantly associated with inherited cardiac conditions and cancer predisposition syndromes. These findings highlight the importance of including underrepresented populations in genomic research and emphasize the need to establish provisions for the return of clinically actionable results to biobank participants, supported by access to genetic counseling.

Conclusion: Our results advocate for the integration of population-specific genomic data into national precision medicine frameworks, particularly for small or isolated populations where tailored approaches to variant curation and clinical translation are required. This study provides the first baseline estimate of actionable SFs in the Maltese population and offers insights for advancing precision medicine frameworks.