Whole exome sequencing as a diagnostic adjunct to clinical testing in fetuses with structural abnormalities
- 1 April 2018
- journal article
- research article
- Published by Wiley in Ultrasound in Obstetrics & Gynecology
- Vol. 51 (4), 493-502
- https://doi.org/10.1002/uog.18915
Abstract
ObjectivesTo 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. MethodsKaryotyping, 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. ResultsOverall, 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). ConclusionsWES 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 (c) 2017 ISUOG. Published by John Wiley & Sons Ltd.Funding Information
- National Natural Science Foundation of China (81 571 448, 81 501 267)
This publication has 25 references indexed in Scilit:
- Promises, pitfalls and practicalities of prenatal whole exome sequencingPrenatal Diagnosis, 2018
- Human exposure to environmental contaminants and congenital anomalies: a critical reviewCritical Reviews in Toxicology, 2016
- Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasoundHuman Molecular Genetics, 2014
- Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian DisordersThe New England Journal of Medicine, 2013
- Implementation of high‐resolution SNP arrays in the investigation of fetuses with ultrasound malformations: 5 years of clinical experienceClinical Genetics, 2013
- Use of prenatal chromosomal microarray: prospective cohort study and systematic review and meta-analysisUltrasound in Obstetrics & Gynecology, 2013
- PRENATAL CYTOGENETIC RESULTS FROM CASES REFERRED FOR 44 DIFFERENT TYPES OF ABNORMAL ULTRASOUND FINDINGSPrenatal Diagnosis, 1996
- Congenital MalformationsThe New England Journal of Medicine, 1983
- Congenital MalformationsThe New England Journal of Medicine, 1983
- Benefits of Ultrasonic Screening of a Pregnant PopulationActa Obstetricia et Gynecologica Scandinavica, 1978