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. 2023 Apr;43(4):527-543.
doi: 10.1002/pd.6314. Epub 2023 Feb 5.

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

Brigitte H W Faas  1 , Dineke Westra  1 , Sonja A de Munnik  1   2 , Maartje van Rij  1 , Carlo Marcelis  1 , Sara Joosten  1 , Ingrid Krapels  2 , Vivian Vernimmen  2 , Malou Heijligers  2 , Marjolein H Willemsen  1 , Nicole de Leeuw  1 , Tuula Rinne  1 , Rolph Pfundt  1 , Sanne P Smeekens  1 , Sander P A Stegmann  2 , Merryn Macville  2 , Esther Sikkel  3 , Audrey Coumans  4 , Lia Wijnberger  5 , Irma Derks  1 , Josefa van Lent-Albrechts  2 , Tom Hofste  1 , Raoul Timmermans  1 , Janneke van den End  1 , Servi J C Stevens  2 , Ilse Feenstra  1
Affiliations

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

Brigitte H W Faas et al. Prenat Diagn. 2023 Apr.

Abstract

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.

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References

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