3 years ago

Whole exome sequencing as a diagnostic adjunct to clinical testing in a tertiary referral cohort of 3988 fetuses with structural abnormalities

Can Liao, Li Zhen, Xin Yang, Fao-Tao Li, Yan-mei Ou, Jian Li, Jin Han, Ru Li, Fang Fu, Dong-zhi Li, Min Pan, Yan Li, Xiang-yi Jing, Dan Wang, Ting-ying Lei, Zhi-Qiang Nie
Objectives To evaluate the diagnostic yield of exome sequencing in diagnosing monogenic disorders in fetuses with structural malformations and to describe the information on pathogenic variants that is provided by exome sequencing. Methods Sequentially performed karyotyping, chromosomal microarray analysis(CMA) and WES on a retrospectively series of fetuses with structural abnormalities, diagnostic rates of three techniques overall and for phenotypic subgroups, and informations on pathogenic variants identified by exome sequencing. Results Overall, 18.2% (720/3949) of the fetal cases had an abnormal karyotype. Pathogenic CNVS were detected in 8.2%(138/1680) of the fetuses that underwent CMA after normal karyotype results. 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 samples and proband-only samples were 26.5% (13 of 49 cases) and 23.1% (34 of 147 cases), respectively. The variants of uncertain significance (VOUS) in the cohort was 12.8%(25/196), among which, 22 variants were identified in the fetal proband group(15%,22/147) and 3 were in the fetus-mother-father trio group(6.1%,3/49). The incidental finding rate in our series was 6.1% (12/196). Conclusions Exome sequencing is a promising method for the identification of genetic variants that cause structural abnormalities in fetuses with normal results on karyotype and CMA. This enhanced diagnostic yield has significantly potential to improve the clinical management of pregnancies and better inform the reproductive decisions of affected families.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/uog.18915

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