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. 2020 Sep;40(10):1300-1309.
doi: 10.1002/pd.5781. Epub 2020 Jul 20.

A prospective study on rapid exome sequencing as a diagnostic test for multiple congenital anomalies on fetal ultrasound

Nicole Corsten-Janssen  1 , Katelijne Bouman  1 , Janouk C D Diphoorn  1 , Arjen J Scheper  1 , Rianne Kinds  1 , Julia El Mecky  1   2 , Hanna Breet  1 , Joke B G M Verheij  1 , Ron Suijkerbuijk  1 , Leonie K Duin  3 , Gwendolyn T R Manten  4 , Irene M van Langen  1 , Rolf H Sijmons  1 , Birgit Sikkema-Raddatz  1 , Helga Westers  1 , Cleo C van Diemen  1
Affiliations

A prospective study on rapid exome sequencing as a diagnostic test for multiple congenital anomalies on fetal ultrasound

Nicole Corsten-Janssen et al. Prenat Diagn. 2020 Sep.

Abstract

Objective: Conventional genetic tests (quantitative fluorescent-PCR [QF-PCR] and single nucleotide polymorphism-array) only diagnose ~40% of fetuses showing ultrasound abnormalities. Rapid exome sequencing (rES) may improve this diagnostic yield, but includes challenges such as uncertainties in fetal phenotyping, variant interpretation, incidental unsolicited findings, and rapid turnaround times. In this study, we implemented rES in prenatal care to increase diagnostic yield.

Methods: We prospectively studied 55 fetuses. Inclusion criteria were: (a) two or more independent major fetal anomalies, (b) hydrops fetalis or bilateral renal cysts alone, or (c) one major fetal anomaly and a first-degree relative with the same anomaly. In addition to conventional genetic tests, we performed trio rES analysis using a custom virtual gene panel of ~3850 Online Mendelian Inheritance in Man (OMIM) genes.

Results: We established a genetic rES-based diagnosis in 8 out of 23 fetuses (35%) without QF-PCR or array abnormalities. Diagnoses included MIRAGE (SAMD9), Zellweger (PEX1), Walker-Warburg (POMGNT1), Noonan (PTNP11), Kabuki (KMT2D), and CHARGE (CHD7) syndrome and two cases of Osteogenesis Imperfecta type 2 (COL1A1). In six cases, rES diagnosis aided perinatal management. The median turnaround time was 14 (range 8-20) days.

Conclusion: Implementing rES as a routine test in the prenatal setting is challenging but technically feasible, with a promising diagnostic yield and significant clinical relevance.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Logistics of rapid prenatal diagnostic testing in the study setting. Panel A (top) shows a realistic, common scenario of inclusion for a fetus with ultrasound anomalies. The collection of fetal material via chorionic villus sampling/amniocentesis is typically scheduled on fixed days of the week, which allows the subsequent genetic diagnostic workflow to be scheduled, including QF‐PCR, SNP‐array, and rES. Panel B (bottom) shows the observed delays in the workflow with the additional time spent on such delays in days. MDT, multidisciplinary team; QF‐PCR, quantitative fluorescent‐polymerase chain reaction; rES, rapid exome sequencing; SNP‐array, single nucleotide polymorphism‐array [Colour figure can be viewed at wileyonlinelibrary.com]
FIGURE 2
FIGURE 2
Inclusion of fetuses with ultrasound anomalies for rES. ES, exome sequencing; QF‐PCR, quantitative fluorescent‐polymerase chain reaction; rES, rapid exome sequencing; SNP‐array, single nucleotide polymorphism‐array [Colour figure can be viewed at wileyonlinelibrary.com]
See this image and copyright information in PMC

References

    1. Eurocat update: short report congenital anomalies Northern Netherlands 1981–2017 (update); 2019. www.eurocat.umcg.nl
    1. Fleurke‐Rozema JH, Bakker MK, Snijders RJM, Bilardo CM. Uptake of the 20‐week scan and the detection rate of selected sonomarkers and structural congenital anomalies (Chapter 8 thesis) In: Fleurke‐Rozema JH, ed. Impact of the 20‐week scan. Groningen, The Netherlands: Rijksuniversiteit Groningen; 2017. https://www.rug.nl/research/portal/files/46538014/Chapter_8.pdf.
    1. Best S, Wou K, Vora N, van der Veyver IB, Wapner R, Chitty LS. Promises, pitfalls and practicalities of prenatal whole exome sequencing. Prenat Diagn. 2018;38(1):10‐19. - PMC - PubMed
    1. Leung GKC, Mak CCY, Fung JLF, et al. Identifying the genetic causes for prenatally diagnosed structural congenital anomalies (SCAs) by whole‐exome sequencing (WES). BMC Med Genomics. 2018;11(1):93. - PMC - PubMed
    1. The International Society for Prenatal Diagnosis , The Society for Maternal and Fetal Medicine , The Perinatal Quality Foundation . Joint Position Statement from the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) on the use of genome‐wide sequencing for fetal diagnosis. Prenatal Diagn. 2018;38(1):6‐9. - PubMed

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