title: High Levels of Sample-to-Sample Variation Confound Data Analysis for Non-Invasive Prenatal Screening of Fetal Microdeletions.
abstract: Our goal was to test the hypothesis that inter-individual genomic copy number variation in control samples is a confounding factor in the non-invasive prenatal detection of fetal microdeletions via the sequence-based analysis of maternal plasma DNA. The database of genomic variants (DGV) was used to determine the "Genomic Variants Frequency" (GVF) for each 50kb region in the human genome. Whole genome sequencing of fifteen karyotypically normal maternal plasma and six CVS DNA controls samples was performed. The coefficient of variation of relative read counts (cv.RTC) for these samples was determined for each 50kb region. Maternal plasma from two pregnancies affected with a chromosome 5p microdeletion was also sequenced, and analyzed using the GCREM algorithm. We found strong correlation between high variance in read counts and GVF amongst controls. Consequently we were unable to confirm the presence of the microdeletion via sequencing of maternal plasma samples obtained from two sequential affected pregnancies. Caution should be exercised when performing NIPT for microdeletions. It is vital to develop our understanding of the factors that impact the sensitivity and specificity of these approaches. In particular, benign copy number variation amongst controls is a major confounder, and their effects should be corrected bioinformatically.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, United States of America.|Center for Fetal Medicine, Magee-Womens Research Institute, Pittsburgh, PA, United States of America.
authors.forename: Tianjiao
authors.initials: T
authors.lastname: Chu
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, United States of America.|Center for Fetal Medicine, Magee-Womens Research Institute, Pittsburgh, PA, United States of America.
authors.forename: Suveyda
authors.initials: S
authors.lastname: Yeniterzi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, United States of America.|Center for Fetal Medicine, Magee-Womens Research Institute, Pittsburgh, PA, United States of America.
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Yatsenko
authors.affiliation: Center for Fetal Medicine, Magee-Womens Research Institute, Pittsburgh, PA, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Dunkel
authors.affiliation: Center for Fetal Medicine, Magee-Womens Research Institute, Pittsburgh, PA, United States of America.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Shaw
authors.affiliation: Center for Fetal Medicine, Magee-Womens Research Institute, Pittsburgh, PA, United States of America.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Bunce
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, United States of America.|Center for Fetal Medicine, Magee-Womens Research Institute, Pittsburgh, PA, United States of America.
authors.forename: David G
authors.initials: DG
authors.lastname: Peters
mesh_terms: D002872:Chromosome Deletion; D015986:Confounding Factors, Epidemiologic; D004247:DNA / Q000235:genetics; D005260:Female; D005333:Fetus; D015894:Genome, Human; D006801:Humans; D011247:Pregnancy; D011296:Prenatal Diagnosis; D015203:Reproducibility of Results
chemical_list: D004247:DNA