Whole exome sequencing as a diagnostic adjunct to clinical testing in fetuses with structural abnormalities

• Published in: Ultrasound in obstetrics & gynecology Vol. 51; no. 4; pp. 493 - 502
• Main Authors: Fu, F., Li, R., Li, Y., Nie, Z.‐Q., Lei, T., Wang, D., Yang, X., Han, J., Pan, M., Zhen, L., Ou, Y., Li, J., Li, F.‐T., Jing, X., Li, D., Liao, C.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-04-2018; Wiley Subscription Services, Inc
• Subjects: Abnormalities; chromosomal microarray analysis; Congenital diseases; Copy number; Diagnostic systems; fetal structural anomalies; Fetuses; Genetic diversity; Genetic variance; genetic variants; genotype‐phenotype analysis; Magnetic resonance imaging; Medical diagnosis; prenatal diagnosis; Quantitative analysis; Subgroups; Ultrasound; whole exome sequencing; genetic variants; genotype-phenotype analysis; prenatal diagnosis; fetal structural anomalies; whole exome sequencing; chromosomal microarray analysis
• ISSN: 0960-7692; 1469-0705
• DOI: 10.1002/uog.18915

Objectives
To evaluate the diagnostic yield of prenatal whole exome sequencing (WES) for monogenic disorders in fetuses with structural malformations and normal results on cytogenetic testing, and to describe information on pathogenic variants that is provided by WES.
Methods
Karyotyping, chromosomal microarray analysis (CMA) and WES were performed sequentially on stored samples from a cohort of 3949 pregnancies with fetal structural abnormalities detected on ultrasound and/or magnetic resonance imaging, referred between January 2011 and December 2015. Diagnostic rates of the three techniques were investigated overall, for phenotypic subgroups and for proband‐only vs fetus–mother–father samples. Information on pathogenic variants was identified by WES.
Results
Overall, 18.2% (720/3949) of fetuses had an abnormal karyotype. Pathogenic copy number variants were detected on CMA in 8.2% (138/1680) of fetuses that had a normal karyotype result. WES performed on a subgroup of 196 fetuses with normal CMA and karyotype results revealed the putative genetic variants responsible for the abnormal phenotypes in 47 cases (24%). The molecular diagnosis rates for fetus–mother–father and proband‐only samples were 26.5% (13/49) and 23.1% (34/147), respectively. Variants of uncertain significance were detected in 12.8% (25/196) of fetuses, of which 22 were identified in the fetal proband‐only group (15%; 22/147) and three in the fetus–mother–father group (6.1%; 3/49). The incidental finding rate was 6.1% (12/196).
Conclusions
WES is a promising method for the identification of genetic variants that cause structural abnormalities in fetuses with normal results on karyotyping and CMA. This enhanced diagnostic yield has the potential to improve the clinical management of pregnancies and to inform better the reproductive decisions of affected families. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.