Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification

Previously, carrier screening has been used in at-risk and specific ethnic populations, or for a limited number of diseases.  The broader screening approach, called expanded carrier screening, was endorsed in 2017 by the American College of Obstetricians and Gynecologists as an acceptable strategy for preconception and prenatal carrier screening.  This is expected to have a significant clinical impact, as targeted screening approaches likely have missed a large number of affected pregnancies due to the limited conditions tested, the unknown ethnic ancestry of many individuals, and the fact that the majority of children born with a genetic disease have no family history of the condition. When provided with results that their pregnancy is at-risk for a severe condition, study show approximately 80% of such couples pursue alternative reproductive options.  Given these consequences and the relative rarity of the included diseases, expanded carrier screening panels must have a high detection rate to correctly identify at-risk couples, and to minimize the residual risk when only one partner is tested positive.  Though next generation sequencing has revolutionized genetic testing as a whole, advances in detecting copy number variants by next generation sequencing have been critical to improving the analytical quality of expanded carrier screening panels. An original research article appearing in the July 2018 issue of Clinical Chemistry describes these achievements while establishing the analytical validity of expanded carrier screening and quantifying how many pregnancies could be impacted by this approach in the general U.S. population.