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

Ultrasound Obstet Gynecol. 2018 Apr;51(4):493-502. 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.

Keywords: chromosomal microarray analysis; fetal structural anomalies; genetic variants; genotype-phenotype analysis; prenatal diagnosis; whole exome sequencing.

Publication types

  • Evaluation Study

MeSH terms

  • Abnormal Karyotype*
  • Abnormalities, Multiple / diagnostic imaging
  • Abnormalities, Multiple / genetics*
  • DNA Copy Number Variations
  • Down Syndrome / diagnosis
  • Down Syndrome / genetics*
  • Exome Sequencing / statistics & numerical data*
  • Female
  • Humans
  • Karyotyping / statistics & numerical data
  • Oligonucleotide Array Sequence Analysis / statistics & numerical data
  • Polymerase Chain Reaction
  • Predictive Value of Tests
  • Pregnancy
  • Retrospective Studies
  • Ultrasonography, Prenatal / statistics & numerical data