Secondary ACMG and non-ACMG genetic findings in a multiethnic cohort of 16,713 pediatric participants

Purpose

Clinical next-generation sequencing is an effective approach for identifying pathogenic sequence variants that are medically actionable for participants and families but are not associated with the participant’s primary diagnosis. These variants are called secondary findings (SFs). According to the literature, there is no report of the types and frequencies of SFs in a large pediatric cohort that includes substantial African-American participants. We sought to investigate the types (including American College of Medical Genetics and Genomics [ACMG] and non-ACMG-recommended gene lists), frequencies, and rates of SFs, as well as the effects of SF disclosure on the participants and families of a large pediatric cohort at the Center for Applied Genomics at The Children’s Hospital of Philadelphia.

Methods

We systematically identified pathogenic (P) and likely pathogenic (LP) variants in established disease-causing genes, adhering to ACMG v3.2 secondary finding guidelines and beyond. For non-ACMG SFs, akin to incidental findings in clinical settings, we utilized a set of criteria focusing on pediatric onset, high penetrance, moderate to severe phenotypes, and the clinical actionability of the variants. This criteria-based approach was applied rather than using a fixed gene list to ensure that the variants identified are likely to affect participant health significantly. To identify and categorize these variants, we used a clinical-grade variant classification standard per ACMG/AMP recommendations; additionally, we conducted a detailed literature search to ensure a comprehensive exploration of potential SFs relevant to pediatric participants.

Results

We report a distinctive distribution of 1464 P/LP SF variants in 16,713 participants. There were 427 unique variants in ACMG genes and 265 in non-ACMG genes. The most frequently mutated genes among the ACMG and non-ACMG gene lists were TTR(41.6%) and CHEK2 (7.16%), respectively. Overall, variants of possible medical importance were found in 8.76% of participants in both ACMG (5.81%) and non-ACMG (2.95%) genes.

Conclusion

Our study revealed that 8.76% of a large, multiethnic pediatric cohort carried actionable secondary genetic findings, with 5.81% in ACMG genes and 2.95% in non-ACMG genes. These findings emphasize the importance of including diverse populations in genetic research to ensure that all groups benefit from early identification of disease risks. Our results provide a foundation for expanding the ACMG gene list and improving clinical care through early interventions.