Expanded preconception carrier screening (ECS) identifies at-risk couples (ARCs) for multiple diseases. ECS reports currently include only pathogenic/likely pathogenic variants (P/LPVs). Variants of unknown significance (VUS) are not reported, unlike genomic or chromosomal array test results in other post/prenatal settings. Couples who are P/LP and VUS carriers (P/LP*VUS) may be at risk, particularly in genes with high P/LP carrier rates. We examined the possible contribution of P/LP*cVUS (coding, nonsynonymous VUS) matings to ECS yield in an Ashkenazi Jewish cohort, a population with well-established preconception screening.
We analyzed 672 Ashkenazi Jewish genome sequences (225,456 virtual matings) for variants in three different gene sets and calculated the rates of P/LP*P/LP and P/LP*cVUS matings.
Across 180 genes, we identified 4671 variants: 144 (3.1%) P/LP and 1963 (42%) VUS. Across gene sets, the proportion of P/LP*P/LP and P/LP*cVUS ARCs was 2.7–3.8% and 6.8–7.5%, respectively.
Disregarding VUS in ECS may miss ARCs. Even if only 10% of couples currently classified as P/LP*cVUS are ultimately reclassified as P/LP*P/LP, ECS yield would increase by ≈20%. While current understanding of VUS precludes VUS reporting in ECS, these findings underscore the importance of VUS reclassification. This will crucially depend on enlarging population frequency databases, especially of affected individuals.
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S.C. thanks the Israel Science Foundation Grant 407/17 and the Abisch Frenkel Foundation. We thank the Ashkenazi Genome Consortium for the AJ genomic data.
S.C. is a paid consultant to MyHeritage. D.M.B. declares stock ownership and compensation from Igentify, where he serves as the Chief Executive Officer. The other authors declare no conflicts of interest.
Access to the data was provided by The Ashkenazi Genome Consortium (TAGC).7 Written informed consent was obtained from all participants and institutional review board (IRB) approval was obtained from all participating institutions. In the United States: Albert Einstein College of Medicine, New York, NY; Columbia University, New York, NY; Mount Sinai School of Medicine, New York, NY; New York University, New York, NY; North Shore University Hospital–Long Island Jewish Medical Center, NY; Yale University, New Haven, CT; University of Pittsburgh, Pittsburgh, PA; Johns Hopkins University, Baltimore, MD; Cedars-Sinai Medical Center, Los Angeles, CA. In Canada: The University of Toronto, Toronto. In Israel: The Hebrew University of Jerusalem, Jerusalem; Tel Aviv Sourasky Medical Center, Tel Aviv; Rambam Medical Center, Haifa; The National Genetics Ethics Committee of the Israeli Ministry of Health. (See Supplementary materials and methods for references.)
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Fridman, H., Behar, D.M., Carmi, S. et al. Preconception carrier screening yield: effect of variants of unknown significance in partners of carriers with clinically significant variants. Genet Med (2019) doi:10.1038/s41436-019-0676-x
- preconception expanded carrier screening
- variant classification
- Ashkenazi Jewish genetics