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Whole exome sequencing as a diagnostic adjunct to clinical testing in fetuses with structural abnormalities.
Ultrasound Obstet Gynecol. 2018 Apr; 51(4):493-502.UO

Abstract

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.

Authors+Show Affiliations

Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.Guanzghou Umbilical Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.Epidemiology Division, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangzhou, Guangdong, China.Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.

Pub Type(s)

Evaluation Study
Journal Article

Language

eng

PubMed ID

28976722

Citation

Fu, F, et al. "Whole Exome Sequencing as a Diagnostic Adjunct to Clinical Testing in Fetuses With Structural Abnormalities." Ultrasound in Obstetrics & Gynecology : the Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology, vol. 51, no. 4, 2018, pp. 493-502.
Fu F, Li R, Li Y, et al. Whole exome sequencing as a diagnostic adjunct to clinical testing in fetuses with structural abnormalities. Ultrasound Obstet Gynecol. 2018;51(4):493-502.
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. (2018). Whole exome sequencing as a diagnostic adjunct to clinical testing in fetuses with structural abnormalities. Ultrasound in Obstetrics & Gynecology : the Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology, 51(4), 493-502. https://doi.org/10.1002/uog.18915
Fu F, et al. Whole Exome Sequencing as a Diagnostic Adjunct to Clinical Testing in Fetuses With Structural Abnormalities. Ultrasound Obstet Gynecol. 2018;51(4):493-502. PubMed PMID: 28976722.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Whole exome sequencing as a diagnostic adjunct to clinical testing in fetuses with structural abnormalities. AU - Fu,F, AU - Li,R, AU - Li,Y, AU - Nie,Z-Q, AU - Lei,T, AU - Wang,D, AU - Yang,X, AU - Han,J, AU - Pan,M, AU - Zhen,L, AU - Ou,Y, AU - Li,J, AU - Li,F-T, AU - Jing,X, AU - Li,D, AU - Liao,C, PY - 2016/12/05/received PY - 2017/09/21/revised PY - 2017/09/22/accepted PY - 2017/10/5/pubmed PY - 2018/9/25/medline PY - 2017/10/5/entrez KW - chromosomal microarray analysis KW - fetal structural anomalies KW - genetic variants KW - genotype-phenotype analysis KW - prenatal diagnosis KW - whole exome sequencing SP - 493 EP - 502 JF - Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology JO - Ultrasound Obstet Gynecol VL - 51 IS - 4 N2 - 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. SN - 1469-0705 UR - https://www.unboundmedicine.com/medline/citation/28976722/Whole_exome_sequencing_as_a_diagnostic_adjunct_to_clinical_testing_in_fetuses_with_structural_abnormalities_ L2 - https://doi.org/10.1002/uog.18915 DB - PRIME DP - Unbound Medicine ER -