Optimizing Gene Panels for Equitable Reproductive Carrier Screening: the "Goldilocks" Approach.

Abstract

Background: Professional organizations recommend pan-ancestry carrier screening for autosomal recessive (AR) and X-linked (XL) conditions. Advances in DNA sequencing allow for analysis of hundreds of genes, but the optimal number of genes for carrier screening remains unclear. The American College of Medical Genetics and Genomics (ACMG) has proposed a tiered approach, recommending screening for 113 genes.

Methods: We analyzed ClinVar and gnomAD v4.1.0 for genes associated with serious AR and XL conditions and modeled screening performance across panels of varying composition and size in diverse genetic ancestries. We also reevaluated the ACMG gene list using this updated gnomAD data.

Results: We identified potential inconsistencies in the ACMG gene lists, particularly in carrier test performance (which we define as positive yield) for underrepresented genetic ancestry groups. Modeling of population data for 1,310 genes revealed that screening 152, 248, 531 and 725 genes achieves 90%, 95%, 99% and 99.7% positive yield in couples, respectively. Real-world data from screening more than 60,000 couples validated our modeling.

Conclusion: Our methodology optimizes gene content for carrier screening panels for diverse ancestry groups, providing a mechanism to continually update guidelines, ensure consistency with genomic population data and improve equity across populations.