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Importance of complete phenotyping in prenatal whole exome sequencing

Human genetics, 2018-02, Vol.137 (2), p.175-181 [Peer Reviewed Journal]

Springer-Verlag GmbH Germany, part of Springer Nature 2018 ;COPYRIGHT 2018 Springer ;Human Genetics is a copyright of Springer, (2018). All Rights Reserved. ;ISSN: 0340-6717 ;EISSN: 1432-1203 ;DOI: 10.1007/s00439-017-1860-1 ;PMID: 29392406

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Title:
Importance of complete phenotyping in prenatal whole exome sequencing
Author: Aarabi, Mahmoud ; Sniezek, Olivia ; Jiang, Huaiyang ; Saller, Devereux N. ; Bellissimo, Daniel ; Yatsenko, Svetlana A. ; Rajkovic, Aleksandar
Subjects: Base pairs ; Biomedical and Life Sciences ; Biomedicine ; Birth ; Birth defects ; Chromosomes ; Congenital defects ; DNA microarrays ; DNA sequencing ; Fetuses ; Gene deletion ; Gene Function ; Genotypes ; Holoprosencephaly ; Human Genetics ; Limiting factors ; Magnetic resonance imaging ; Metabolic Diseases ; Molecular Medicine ; Original Investigation ; Phenotypes ; Phenotyping ; Pregnant women ; Prenatal development ; Prenatal diagnosis ; Ultrasonic imaging ; Ultrasound
Is Part Of: Human genetics, 2018-02, Vol.137 (2), p.175-181
Description: 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.
Publisher: Berlin/Heidelberg: Springer Berlin Heidelberg
Language: English
Identifier: ISSN: 0340-6717
EISSN: 1432-1203
DOI: 10.1007/s00439-017-1860-1
PMID: 29392406
Source: ProQuest Central

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Importance of complete phenotyping in prenatal whole exome sequencing

Springer-Verlag GmbH Germany, part of Springer Nature 2018 ;COPYRIGHT 2018 Springer ;Human Genetics is a copyright of Springer, (2018). All Rights Reserved. ;ISSN: 0340-6717 ;EISSN: 1432-1203 ;DOI: 10.1007/s00439-017-1860-1 ;PMID: 29392406

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