The potential diagnostic yield of Whole Exome Sequencing in 391 pregnancies complicated by fetal ultrasound anomalies and with normal chromosomal microarray results
Kathleen Romijn1, Malgorzata Srebniak1, Marike Polak2, Alice Brooks1, Yolande van Bever1, Grazia Verheijen-Mancini1, Marieke Joosten1, Lutgarde Govaerts1, Joan Kromosoeto1, Maarten F.C.M. Knapen3, Attie Go4, Marjon van Slegtenhorst1, Hennie Bruggenwirth1, Diane Van Opstal4, Lies Hoefsloot1, Robert-Jan Galjaard1, Karin Diderich1
1Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands
2Institute of Psychology, Erasmus University Rotterdam, Rotterdam, Netherlands
3Department of Obstetrics and Gynecology, Erasmus MC and Foundation Prenatal Screening Southwest Region of the Netherlands, Rotterdam, Netherlands
4Erasmus Medical Center, Rotterdam, Netherlands
Objectives
The aim of this retrospective cohort study is to determine the potential diagnostic yield of prenatal whole exome sequencing (WES) in fetuses with ultrasound abnormalities and with normal chromosomal microarray results. In cases of fetal abnormalities, it is now standard practice to perform chromosomal microarray, but whole genome testing for single-gene mutations is not yet routinely offered. Possibly, couples who have chosen for prenatal array testing would also choose for prenatal WES to discover the cause of the ultrasound anomaly found in their pregnancy.
Method
In the period January 1st, 2013- January 1st, 2017 845 pregnant women with fetal ultrasound anomalies who received normal microarray results were referred for additional genetic counselling. 391 couples wanted additional molecular testing to be performed. The couples were not selected based on the severity of ultrasound anomalies. Most of the couples received only targeted molecular testing and in only 131 cases WES (large panels or open exome) was performed (after birth). The results of these molecular tests were evaluated retrospectively, regardless of the time of the genetic diagnosis (before or after birth).
Results
In 81 (20.7%) of 391 fetuses molecular testing provided a genetic diagnosis with identification of (likely) pathogenic variants in 58 different candidate genes. In 84% of the abnormal cases (68/81) the variant was clearly pathogenic and would be reported prenatally regardless of the fetal phenotype. In the remaining cases, additional phenotypic data were necessary for the interpretation of the molecular results and clinical geneticists could finally conclude that these findings were (very likely) causal. In one diagnosed case an additional unexpected/incidental finding was detected, which concerned an early onset syndromic disorder.
Conclusions
Our retrospective cohort study shows that WES, if routinely offered to patients in a prenatal setting, would significantly increase the diagnostic yield in fetuses with ultrasound abnormalities. However because not all fetuses were tested with WES and some of the investigations were not yet completed at the time of the study, we presume that this yield of 20.7% could be an underestimation. Concluding, WES if performed prenatally would lead to an early diagnosis of a genetic disorder in a significant percentage of cases irrespective of the (incomplete) fetal phenotype.
