2018 ISPD Conference

Implementing fast whole exome sequencing (WES) as diagnostic test for fetal multiple congenital anomalies on ultrasound
Nicole Corsten-Janssen1, K. Bouman2, Joke Verheij1, Julia El Mecky1, Helga Westers1, Rianne Kinds1, Ron Suijkerbuijk3, Beike Leegte1, Arjen Scheper1, Birgit Sikkema-Raddatz4, Richard Sinke4, Irene Van Langen5, Rolf Sijmons1, Cleo van Diemen1

1University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands
2University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands, Groningen, Groningen, Netherlands
3Department of Genetics, University Medical Centre Groningen, University of Groningen, 9700 RB, Groningen, Netherlands
4Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands
5University Medical Center Groningen, University of Groningen, Groningen, Netherlands
Objectives
Identifying the cause of fetal anomalies seen on ultrasound is paramount to improve reproductive choice and/or perinatal management. The conventional test (chromosomal microarray) leads to a diagnosis in  approximately 25% of fetuses with multiple congenital anomalies (MCA) on ultrasound. WES  is a promising technique to improve diagnostic yield. However, implementing WES in prenatal setting is challenging due to uncertainties around fetal phenotyping, required short turnaround times, and technical and ethical handling of incidental findings and variant interpretation. Here, we discuss the implementation of WES as a routine fast test for fetuses with MCA on ultrasound in our center.
Methods
Phase 1 (concluded): Blind retrospective WES analysis of six fetuses with known postnatal genetic diagnosis to test if this diagnosis could be made on the fetal phenotype only. Variants were filtered using human phenotype ontology (HPO) or using our  custom virtual prenatal gene panel (all known disease genes, excluding late-onset diseases).
Phase 2 (Starting March 5th): Prospective study of rapid trio WES analysis in addition to conventional genetic tests for fetuses with two or more congenital malformations on ultrasound. Measures: diagnostic yield; turnaround times; clinical consequences; differences in prenatal and postnatal genotype interpretation; and impact on couples and caregivers.
Results
Phase 1: Five of six known diagnosis could be confirmed by WES using our prenatal gene panel. HPO was not helpful in filtering variants. One causal pathogenic PTPN11 mutation was missed due to generally low capture efficiency and thus coverage in WES data. Modeling the WES pipeline shows a theoretical turn-around time of 8 working days  after the invasive procedure, which is sufficient in most cases.
Phase 2: The preliminary results of the prospective study will be available during the conference. Approximately 20 rapid trio WES analysis are expected.
Conclusions
Retrospective analysis and modeling of our pipeline show that implementing WES as a routine test in the prenatal setting is technically feasible  in our center.  With our implementation study we aim to investigate the feasibility, pro’s and con’s of prenatal WES in daily practice.