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



To evaluate the effectiveness and specificity of population-based genomic screening in Alabama.


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.


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.


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.

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Fig. 1
Fig. 2: Differences in genetic variation types between true and false positive variants.
Fig. 3: False positive (FP) findings in the context of race/ethnicity.


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We thank all AGHI participants for their contributions to this study. This study was conducted at the University of Alabama at Birmingham and the HudsonAlpha Institute for Biotechnology and funded by the state of Alabama.

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Correspondence to Gregory M. Cooper PhD.

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B.R.K. discloses a potential conflict of interest as a member of the medical advisory boards of AstraZeneca, SpringWorks, and Genome Medical. The other authors declare no conflicts of interest.

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Bowling, K.M., Thompson, M.L., Gray, D.E. et al. Identifying rare, medically relevant variation via population-based genomic screening in Alabama: opportunities and pitfalls. Genet Med 23, 280–288 (2021).

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


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