A rigorous approach for selection of optimal variant sets for carrier screening with demonstration of clinical utility

Carrier screening for certain diseases is recommended by major medical and Ashkenazi Jewish (AJ) societies. Most carrier screening panels test only for common, ethnic-specific variants. However, with formerly isolated ethnic groups becoming increasingly intermixed, this approach is becoming inadequate. Our objective was to develop a rigorous process to curate all variants, for relevant genes, into a database and then apply stringent clinical validity classification criteria to each in order to retain only those with clear evidence for pathogenicity. The resulting variant set, in conjunction with next-generation DNA sequencing (NGS), then affords the capability for an ethnically diverse, comprehensive, highly specific carrier-screening assay. The clinical utility of our approach was demonstrated by screening a pan-ethnic population of 22,864 individuals for Bloom syndrome carrier status using a BLM variant panel comprised of 50 pathogenic variants. In addition to carriers of the common AJ founder variant, we identified 57 carriers of other pathogenic BLM variants. All variants reported had previously been curated and their clinical validity documented, or were of a type that met our stringent, preassigned validity criteria. Thus, it was possible to confidently report an increased number of Bloom's syndrome carriers compared to traditional, ethnicity-based screening, while not reducing the specificity of the screening due to reporting variants of unknown clinical significance.