Project details


Rapid whole exome sequencing in prenatal genetic diagnostics for ultrasound abnormalities

phenotype-genotype study whole exome sequencing prenatal diagnostics

dr. C.C. van Diemen
dr. H. Westers
drs. K. Bouman
drs. N. Corsten-Jansen

Nature of the research:
Collect clinical information; literature search; phenotype-genotype comparison; identify candidate genes

Fields of study:
obstetrics genetics

Background / introduction
Fetal abnormalities are identified in 2-5% of pregnancies and are responsible for 20% of perinatal deaths. Pregnancy outcome and prognosis vary according to the types of abnormalities detected, and whether they are isolated or multiple. Currently, prenatal testing strategies, including qfPCR, FISH, karyotyping and SNP arrays, are mainly focused on detecting structural genetic aberrations. An underlying genetic etiology can be identified in up to 40% of dysmorphic fetuses, still leaving the majority of cases undiagnosed. We are going to apply the whole exome sequencing (WES) technique to study whether we could improve prenatal genetic diagnostics.

For this project we are looking for a student who wants to do phenotype-genotype analysis for this study.
Research question / problem definition
Can we develop a genetic diagnostic test with which we can give a genetic diagnosis within one week after finding foetal abnormalities with an advanced ultrasound?

To be able to answer this research question, we will perform the following studies:
1. pilot study: retrospective test to study whether the material is suitable for WES DNA diagnostics and to set up inclusion criteria and the procedure for rapid prenatal diagnostics
2. prospective study: offer rapid prenatal diagnostics for one year to a limited group of foetuses with ultrasound abnormalities to determine the diagnostic yield and diagnosis rate
The aim of this study is to come up with the logistics for rapid prenatal next generation sequencing (NGS) diagnostics. This involves the following steps:

a) Determine the types of ultrasound abnormalities and phenotypically characterize these in a standard way (clinical characteristics have to be linked to a gene list)
b) Analyse rapid prenatal NGS diagnostics for selected patients and determine the sensitivity. The data will be analysed “blindly”, the student does not know the clinical diagnosis of the foetus.
c) Set up the procedure for rapid prenatal NGS diagnostics. The minimal amount of DNA and the type of ultrasound abnormalities for which rapid prenatal NGS diagnostics is suited are determined.
d) Compose consent forms and information for the prospective studies. The knowledge that was gained from the rapid new born NGS diagnostics project will be used for this.
Rapid Targeted Genomics in Critically Ill Newborns. van Diemen CC, Kerstjens-Frederikse WS, Bergman KA, de Koning TJ, Sikkema-Raddatz B, van der Velde JK, Abbott KM, Herkert JC, Löhner K, Rump P, Meems-Veldhuis MT, Neerincx PBT, Jongbloed JDH, van Ravenswaaij-Arts CM, Swertz MA, Sinke RJ, van Langen IM, Wijmenga C. Pediatrics. 2017 Oct;140(4). pii: e20162854. doi: 10.1542/peds.2016-2854.

Promises, Pitfalls and Practicalities of Prenatal Whole Exome Sequencing. Best S, Wou K, Vora N, Van den Veyver IB, Wapner R, Chitty LS. Prenat Diagn. 2017 Jun 27. doi: 10.1002/pd.5102.
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