Identifying rare, medically relevant variation via population-based genomic screening in Alabama: opportunities and pitfalls

Kevin M. Bowling, Michelle L. Thompson, David E. Gray, James M.J. Lawlor, Kelly Williams, Kelly M. East, Whitley V. Kelley, Irene P. Moss, Devin M. Absher, E. Christopher Partridge, Anna C.E. Hurst, Jeffrey C. Edberg, Gregory S. Barsh, Bruce R. Korf, Gregory M. Cooper

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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 5369 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. Variants detected within African American individuals were significantly enriched for FPs, likely due to a higher rate of nontargeted 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.

Original languageEnglish
Pages (from-to)280-288
Number of pages9
JournalGenetics in Medicine
Volume23
Issue number2
DOIs
StatePublished - Feb 2021

Keywords

  • clinically actionable
  • diverse population
  • false positive
  • genotyping array
  • population screening

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