Human Genetics

, Volume 137, Issue 2, pp 175–181 | Cite as

Importance of complete phenotyping in prenatal whole exome sequencing

  • Mahmoud Aarabi
  • Olivia Sniezek
  • Huaiyang Jiang
  • Devereux N. Saller
  • Daniel Bellissimo
  • Svetlana A. Yatsenko
  • Aleksandar Rajkovic
Original Investigation

Abstract

Whole exome sequencing (WES) is an emerging technique in prenatal diagnosis. In this retrospective study, we examined diagnostic utility and limitations of WES in prenatal cases with structural birth defects. DNA from 20 trios (fetal and parental), with normal karyotype and microarray findings, underwent WES and variant interpretation at a reference laboratory. The WES results were later re-evaluated in our academic center utilizing prenatal and postnatal phenotyping. Initial analysis using only prenatal ultrasound findings revealed no pathogenic or likely pathogenic variants in 20 pregnancies with structural birth defects. Re-analysis of WES variants and combination of prenatal and postnatal phenotyping yielded pathogenic variants in at least 20% of cases including PORCN gene in a fetus with split-hand/foot malformation, as well as variants of uncertain significance in NEB and NOTCH1 in fetuses with postnatal muscle weakness and Adams–Oliver syndrome, respectively. Furthermore, Sanger sequencing in a patient with holoprosencephaly, elucidated by postnatal MRI, revealed a pathogenic 47-base pairs deletion in ZIC2 which was missed by prenatal WES. This study suggests that incomplete prenatal phenotyping and lack of prenatal ultrasound-genotype databases are the limiting factors for current interpretation of WES data in prenatal diagnosis. Development of prenatal phenotype–genotype databases would significantly help WES interpretation in this setting. Patients who underwent prenatal clinical WES may benefit from the re-analysis based on detailed postnatal findings.

Notes

Acknowledgements

We thank the families for participation in this study.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the University of Pittsburgh Institutional Review Board (#PRO16070068).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Data availability

All the genetic and genomic data generated during this study are included in this manuscript and its supplementary files.

Supplementary material

439_2017_1860_MOESM1_ESM.pdf (663 kb)
Supplementary material 1 (PDF 663 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Mahmoud Aarabi
    • 1
    • 2
  • Olivia Sniezek
    • 3
    • 4
  • Huaiyang Jiang
    • 4
  • Devereux N. Saller
    • 2
  • Daniel Bellissimo
    • 1
    • 2
  • Svetlana A. Yatsenko
    • 1
    • 2
    • 4
    • 5
    • 6
  • Aleksandar Rajkovic
    • 1
    • 2
    • 4
    • 5
    • 6
  1. 1.Medical Genetics and Genomics LaboratoriesMagee-Womens Hospital of UPMCPittsburghUSA
  2. 2.Department of Obstetrics, Gynecology and Reproductive SciencesUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Westminster CollegeNew WilmingtonUSA
  4. 4.Magee-Womens Research InstitutePittsburghUSA
  5. 5.Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  6. 6.Department of Human Genetics, Graduate School of Public HealthUniversity of PittsburghPittsburghUSA

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