Secondary findings in pediatric genomic testing: clinical insights from Turkey

The clinical expansion of whole exome and genome sequencing has raised critical questions regarding the management of secondary findings (SFs), particularly in pediatric populations. We aimed to determine the frequency, characteristics, and familial implications of SFs in a cohort of 980 Turkish pediatric patients, while addressing the ethical and psychological challenges of reporting adult-onset risks. We retrospectively analyzed whole exome sequencing data from 980 pediatric patients. SFs were reviewed based on the 81 genes in the American College of Medical Genetics and Genomics (ACMG) SFs v3.2 list. Only variants classified as Pathogenic (P) or Likely Pathogenic (LP) according to ACMG/Association for Molecular Pathology (AMP) guidelines were reported. The distribution of these variants across clinical disease categories represented by the ACMG SFs gene list (e.g., cancer predisposition, cardiovascular, metabolic) was evaluated. We identified actionable variants in 1.9% of patients. The most commonly affected genes were associated with cancer predisposition syndromes and cardiovascular conditions. This finding is consistent with the eMERGE study, which reported a 3.02% overall frequency of SFs (2.54% within the 59 ACMG-recommended genes), with cancer and cardiac genes being the most commonly reported categories. Differences in typical age of disease onset were noted, potentially impacting clinical management in pediatric settings. Despite most variants being inherited, a positive family history was documented in only one case, underscoring the limitations of family history alone in identifying at-risk individuals. No single gene was overrepresented, and the distribution of identified variants was consistent with what has been observed in other populations.

This study presents the first comprehensive analysis of ACMG v3.2 SFs in a Turkish pediatric population. While consistent with global literature, our findings contribute novel, age and population-specific data. Most identified variants were inherited, underscoring opportunities for early diagnosis and management not only in children but also in asymptomatic parents through cascade screening. These results highlight that the responsible and evidence-based return of SFs in pediatric care requires a balanced approach one that weighs clinical benefit against ethical responsibility. Our findings may inform the integration of genomic screening and policy development in pediatric care, particularly in resource-limited settings.

• Secondary findings (SFs) from clinical genomic sequencing can uncover medically actionable risks unrelated to the primary indication. In pediatric patients, however, the disclosure of SFs-particularly those related to adult-onset conditions-raises ethical concerns regarding autonomy and parental decision-making. While the ACMG recommends returning SFs regardless of age, their guidelines highlight the critical role of pre- and post-test counseling and the option for families to accept or decline such results. • Despite these recommendations, pediatric-specific evidence remains scarce, especially in regions with emerging or resource-limited healthcare systems such as Turkey. Expanding context-specific data is essential for guiding ethically sound and equitable implementation of genomic medicine in pediatric populations.

• This study represents the first pediatric-only analysis of secondary findings in a Turkish cohort using the ACMG v3.2 gene list. Unlike previous Turkish studies with mixed or undefined age groups, it focuses exclusively on children, thereby providing age-specific insights into the prevalence and characteristics of actionable variants. • While most findings involved cancer predisposition and cardiovascular genes, as expected given the ACMG SF list structure, the study contributes unique pediatric data from a region with limited prior representation. Such region-specific pediatric datasets are essential to guide the equitable and context-sensitive implementation of genomic medicine.