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

Clinical Chemistry
Gregory J HoganDale Muzzey

Abstract

By identifying pathogenic variants across hundreds of genes, expanded carrier screening (ECS) enables prospective parents to assess the risk of transmitting an autosomal recessive or X-linked condition. Detection of at-risk couples depends on the number of conditions tested, the prevalence of the respective diseases, and the screen's analytical sensitivity for identifying disease-causing variants. Disease-level analytical sensitivity is often <100% in ECS tests because copy number variants (CNVs) are typically not interrogated because of their technical complexity. We present an analytical validation and preliminary clinical characterization of a 235-gene sequencing-based ECS with full coverage across coding regions, targeted assessment of pathogenic noncoding variants, panel-wide CNV calling, and specialized assays for technically challenging genes. Next-generation sequencing, customized bioinformatics, and expert manual call review were used to identify single-nucleotide variants, short insertions and deletions, and CNVs for all genes except FMR1 and those whose low disease incidence or high technical complexity precluded novel variant identification or interpretation. Screening of 36859 patients' blood or saliva samples reve...Continue Reading

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Citations

Mar 1, 2019·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Rotem Ben-ShacharDale Muzzey
May 1, 2019·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Kyle A BeauchampDale Muzzey
Feb 15, 2019·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Kyle A BeauchampDale Muzzey
Dec 13, 2019·Journal of Community Genetics·Charlotte A Rowe, Caroline F Wright
Oct 13, 2018·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Katherine A Johansen TaberJames D Goldberg
Jul 1, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Kristjan E KaseniitDale Muzzey
Nov 22, 2019·The Journal of Molecular Diagnostics : JMD·Erick R ScottStuart A Scott
Jan 16, 2021·Prenatal Diagnosis·Aishwarya ArjunanKatherine Johansen Taber
Jul 7, 2021·European Journal of Obstetrics, Gynecology, and Reproductive Biology·Jing YangWenyan Wu

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