PT  - JOURNAL ARTICLE
AU  - Kevin M. Bowling
AU  - Michelle L. Thompson
AU  - David E. Gray
AU  - James M.J. Lawlor
AU  - Kelly Williams
AU  - Kelly M. East
AU  - Whitley V. Kelley
AU  - Irene P. Moss
AU  - Devin M. Absher
AU  - E. Christopher Partridge
AU  - Anna C.E. Hurst
AU  - Jeffrey C. Edberg
AU  - Gregory S. Barsh
AU  - Bruce R. Korf
AU  - Gregory M. Cooper
TI  - Identifying rare, medically-relevant genetic variation in a diverse population: opportunities and pitfalls
AID  - 10.1101/2020.05.28.122457
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.28.122457
4099  - http://biorxiv.org/content/early/2020/06/02/2020.05.28.122457.short
4100  - http://biorxiv.org/content/early/2020/06/02/2020.05.28.122457.full
AB  - Purpose To evaluate the effectiveness and specificity of population-based genomic screening in Alabama.Methods The Alabama Genomic Health Initiative (AGHI) has enrolled and evaluated 5,369 participants for the presence of pathogenic/likely pathogenic (P/LP) variants using the Illumina Global Screening Array (GSA), with validation of all P/LP variants via Sanger sequencing in a CLIA-certified laboratory before return of results.Results Among 131 variants identified by the GSA that were evaluated by Sanger sequencing, 67 (51%) were false positives (FP). For 39 of the 67 FP variants, a benign/likely benign variant was present at or near the targeted P/LP variant. Importantly, African-Americans were significantly enriched for FP variants, likely due to a higher rate of non-targeted alternative alleles close to array-targeted P/LP variants.Conclusion In AGHI, we have implemented an array-based process to screen for highly penetrant genetic variants in actionable disease genes. We demonstrate the need for clinical validation of array-identified variants in direct-to-consumer or population testing, especially for diverse populations.Competing Interest StatementThe authors have declared no competing interest.