All‐in‐one whole exome sequencing strategy with simultaneous copy number variant, single nucleotide variant and absence‐of‐heterozygosity analysis in fetuses with structural ultrasound anomalies: A 1‐year experience.

Objective: We performed a 1‐year evaluation of a novel strategy of simultaneously analyzing single nucleotide variants (SNVs), copy number variants (CNVs) and copy‐number‐neutral Absence‐of‐Heterozygosity from Whole Exome Sequencing (WES) data for prenatal diagnosis of fetuses with ultrasound (US) anomalies and a non‐causative QF‐PCR result. Methods: After invasive diagnostics, whole exome parent‐offspring trio‐sequencing with exome‐wide CNV analysis was performed in pregnancies with fetal US anomalies and a non‐causative QF‐PCR result (WES‐CNV). On request, additional SNV‐analysis, restricted to (the) requested gene panel(s) only (with the option of whole exome SNV‐analysis afterward) was performed simultaneously (WES‐CNV/SNV) or as rapid SNV‐re‐analysis, following a normal CNV analysis. Results: In total, 415 prenatal samples were included. Following a non‐causative QF‐PCR result, WES‐CNV analysis was initially requested for 74.3% of the chorionic villus (CV) samples and 45% of the amniotic fluid (AF) samples. In case WES‐CNV analysis did not reveal a causative aberration, SNV‐re‐analysis was requested in 41.7% of the CV samples and 17.5% of the AF samples. All initial analyses could be finished within 2 weeks after sampling. For SNV‐re‐analysis during pregnancy, turn‐around‐times (TATs) varied between one and 8 days. Conclusion: We show a highly efficient all‐in‐one WES‐based strategy, with short TATs, and the option of rapid SNV‐re‐analysis after a normal CNV result. Key points: What is already known about this topic?Exome sequencing has been implemented in prenatal diagnosis, but is usually offered for single nucleotide variant (SNV) analysis only, after a non‐causative copy number variant (CNV) result obtained with array analysis. What does this study add?This study shows the added value of an all‐in‐one strategy of simultaneously analyzing SNVs, CNVs and copy‐number‐neutral absence‐of‐heterozygosity in whole exome sequencing data for pregnancies with fetal ultrasound anomalies and a non‐causative QF‐PCR result. [ABSTRACT FROM AUTHOR]