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

Abstract

AbstractObjectiveWe 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.MethodsAfter 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.ResultsIn 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.ConclusionWe 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.