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. 2018 Oct 25;11(1):93.
doi: 10.1186/s12920-018-0409-z.

Identifying the genetic causes for prenatally diagnosed structural congenital anomalies (SCAs) by whole-exome sequencing (WES)

Gordon K C Leung  1 , Christopher C Y Mak  1 , Jasmine L F Fung  1 , Wilfred H S Wong  1 , Mandy H Y Tsang  1 , Mullin H C Yu  1 , Steven L C Pei  1 , K S Yeung  1 , Gary T K Mok  1 , C P Lee  2 , Amelia P W Hui  2 , Mary H Y Tang  2   3 , Kelvin Y K Chan  2   3 , Anthony P Y Liu  1 , Wanling Yang  1 , P C Sham  4 , Anita S Y Kan  5   6 , Brian H Y Chung  7   8   9
Affiliations

Identifying the genetic causes for prenatally diagnosed structural congenital anomalies (SCAs) by whole-exome sequencing (WES)

Gordon K C Leung et al. BMC Med Genomics. .

Abstract

Background: Whole-exome sequencing (WES) has become an invaluable tool for genetic diagnosis in paediatrics. However, it has not been widely adopted in the prenatal setting. This study evaluated the use of WES in prenatal genetic diagnosis in fetuses with structural congenital anomalies (SCAs) detected on prenatal ultrasound.

Method: Thirty-three families with fetal SCAs on prenatal ultrasonography and normal chromosomal microarray results were recruited. Genomic DNA was extracted from various fetal samples including amniotic fluid, chorionic villi, and placental tissue. Parental DNA was extracted from peripheral blood when available. We used WES to sequence the coding regions of parental-fetal trios and to identify the causal variants based on the ultrasonographic features of the fetus.

Results: Pathogenic mutations were identified in three families (n = 3/33, 9.1%), including mutations in DNAH11, RAF1 and CHD7, which were associated with primary ciliary dyskinesia, Noonan syndrome, and CHARGE syndrome, respectively. In addition, variants of unknown significance (VUSs) were detected in six families (18.2%), in which genetic changes only partly explained prenatal features.

Conclusion: WES identified pathogenic mutations in 9.1% of fetuses with SCAs and normal chromosomal microarray results. Databases for fetal genotype-phenotype correlations and standardized guidelines for variant interpretation in prenatal diagnosis need to be established to facilitate the use of WES for routine testing in prenatal diagnosis.

Keywords: Phenotyping; Prenatal exome; Variants of unknown clinical significance.

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Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (HKU/HA HKW IRB) (Reference number UW14–323). Informed consent was obtained from the parents during pre-test counselling.

Consent for publication

The parents were consented for publication during pre-test counselling.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Pedigrees of the three families with pathogenic mutation(s) identified by WES. The lower panel shows the read alignments at the mutation loci in Integrated Genomics Viewer (IGV)
Fig. 2
Fig. 2
Forest plot showing the diagnostic yield between prenatal studies and postnatal studies. The rectangles represent the diagnostic rate in each study with 95% confidence interval bounds. The diamond in each group represents the combined diagnostic yield with all studies included
Fig. 3
Fig. 3
Forest plot showing the proportion of VUSs among positive cases between prenatal studies and postnatal studies. The rectangles represent the VUS fraction in each study with 95% confidence interval bounds. The diamond in each group represents the combined proportion of VUSs with all studies included
See this image and copyright information in PMC

References

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