Estimating yields of prenatal carrier screening and implications for design of expanded carrier screening panels

Abstract

Purpose: Prenatal genetic carrier screening can identify parents at risk of having a child affected by a recessive condition. However, the conditions/genes most appropriate for screening remain a matter of debate. Estimates of carrier rates across genes are needed to guide construction of carrier screening panels.

Method: We leveraged an exome sequencing database (n = 123,136) to estimate carrier rates across six major ancestries for 415 genes associated with severe recessive conditions.

Results: We found that 32.6% (East Asian) to 62.9% (Ashkenazi Jewish) of individuals are variant carriers in at least one of the 415 genes. For couples, screening all 415 genes would identify 0.17-2.52% of couples as being at risk for having a child affected by one of these conditions. Screening just the 40 genes with carrier rate >1.0% would identify more than 76% of these at-risk couples. An ancestry-specific panel designed to capture genes with carrier rates >1.0% would include 5 to 28 genes, while a comparable panethnic panel would include 40 genes.

Conclusion: Our work guides the design of carrier screening panels and provides data to assist in counseling prospective parents. Our results highlight a high cumulative carrier rate across genes, underscoring the need for careful selection of genes for screening.

Keywords: Mendelian disorder; exome sequencing; expanded carrier screening; genetic counseling; pathogenic variants.