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

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

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...

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Published in:Prenatal diagnosis Vol. 40; no. 10; pp. 1300 - 1309
Main Authors: Corsten‐Janssen, Nicole, Bouman, Katelijne, Diphoorn, Janouk C. D., Scheper, Arjen J., Kinds, Rianne, Mecky, Julia, Breet, Hanna, Verheij, Joke B. G. M., Suijkerbuijk, Ron, Duin, Leonie K., Manten, Gwendolyn T. R., Langen, Irene M., Sijmons, Rolf H., Sikkema‐Raddatz, Birgit, Westers, Helga, Diemen, Cleo C.
Format: Journal Article
Language:English
Published: Chichester, UK John Wiley & Sons, Ltd 01-09-2020
Wiley Subscription Services, Inc
Subjects:
Abnormalities
Arrays
Biomedical materials
CHARGE syndrome
Collagen (type I)
Congenital anomalies
Congenital defects
Cysts
Diagnosis
Diagnostic systems
Diagnostic tests
Edema
Fetuses
Fluorescence
Gene polymorphism
Genetic analysis
Genetic screening
Heredity
Hydrops fetalis
Medical diagnosis
Nucleotides
Original
Osteogenesis
Osteogenesis imperfecta
Phenotyping
Polymorphism
Single-nucleotide polymorphism
Ultrasonic imaging
Ultrasound
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Summary: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.
Bibliography:Funding information
University Medical Center Groningen Healthy Ageing Pilot grant, Grant/Award Number: CDO17.0028/2017‐2/321
Birgit Sikkema‐Raddatz and Helga Westers shared authorship.
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Funding information University Medical Center Groningen Healthy Ageing Pilot grant, Grant/Award Number: CDO17.0028/2017‐2/321
ISSN:0197-3851
1097-0223
DOI:10.1002/pd.5781