Background
In our original study, we utilized clinical next-generation sequencing to identify pathogenic (P) or likely pathogenic (LP) sequence variations that are not associated with a patient's primary indication for testing within a large pediatric cohort. These variations are called secondary findings (SFs). Our cohort was enriched for Black or African-American (AA) children, which comprised 51.8% (8667 subjects) of the total cohort (16713 subjects) at the Center for Applied Genomics at The Children’s Hospital of Philadelphia. The inclusion rate of individuals (adults and pediatrics) with African ancestry in published genome-wide studies is <3% which highlights the unmet need for further genetics research on this population. The strong representation of Black or AA children in our cohort allowed us to present information on the types and frequencies of P/LP SFs primarily affecting Black or AA children and families.

Methods
The original study searched for P/LP variants in disease-causing genes, specifically in 78 American College of Medical Genetics and Genomics (ACMG)-recommended and 93 non-ACMG genes that were defined as SFs in patients of four large pediatric cohorts. The 93 non-ACMG genes were selected after an extensive literature search for relevant genes proposed for addition to the ACMG list. Variants were filtered by P/LP classification as per ACMG/Association for Molecular Pathology (AMP) recommendations, Combined Annotation Dependent Deletion (CADD) vs Mutation Significance Cutoff (MSC) scores, variant type, presence in disease-causing variant databases, and Integrative Genomics Viewer (IGV) visualization for manual variant quality inspection. We divided the patient's P/LP variants into four disease categories: cancer, cardiovascular, metabolic, and miscellaneous. We further divided our patients by self-reported ethnicity.

Results
Black or AA subjects comprised 307/320 (82%) of TTR variants (ACMG), 29/48 (60%) of RYR1 variants (ACMG), and 22/39 (56%) of LDLR variants (ACMG).
Out of 307 Black or AA subjects with P/LP variants in TTR, the most common variant (304) was p.V142I. The other three variants were p.V50M, p.V113M, and p.D119V.
Additionally, Black or AA subjects comprised 335/350 (95%) of G6PD variants (non-ACMG). The most common variant (327) was p.V98M which was excluded from final reports since it has mild clinical manifestations.

Conclusion
These SF data provide valuable insight into common P/LP genetic variations and associated diseases which mainly affect Black or AA children. The implications of identifying most TTR, RYR1, and LDLR gene variants in this underrepresented patient population include: better informed medical management, reproductive planning, and family member genetic testing for Black or AA children and families specifically.

Enrichment of secondary genetic findings of TTR, RYR1, and LDLR in a cohort of 8667 African-American pediatric subjects

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Enrichment of secondary genetic findings of TTR, RYR1, and LDLR in a cohort of 8667 African-American pediatric subjects

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