Implementation of exome sequencing in fetal diagnostics—Data and experiences from a tertiary center in Denmark

Abstract

Introduction:Applying whole-exome sequencing (WES) for the diagnosis of diseases in children has shown significant diagnostic strength compared with chromosomal microarray. WES may also have the potential of adding clinically relevant prenatal information in cases where a fetus is found to have structural anomalies. We present results from the first fetal exomes performed in a tertiary center in Denmark. Material and methods: Couples/expectant parents were included in Central DenmarkRegion from July 2016 to March 2019. Inclusion was not systematic, but where one or more fetal malformations or severe fetal hydrops were detected, and a specific diagnosis had not been obtained by chromosomal microarray. WES was performed in ongoing pregnancies (N = 11), after intrauterine demise (N = 5), or after termination of pregnancy based on ultrasound findings (N = 19). In most cases, a trio format was applied comprising fetal and parental DNA.Results: WES was performed in 35 highly selected fetal cases. Pathogenic variants, or variants likely to explain the phenotype, were detected in 9/35 (26%). Variants of uncertain significance were detected in 7/35 (20%) and there was one secondary finding (3%). Out of the 11 ongoing pregnancies, four reached a genetic diagnosis (36%). Detection rate was highest in cases of multisystem anomalies (7/13, 54%).WES was completed in all three trimesters and both autosomal dominant, autosomal recessive and X-linked inheritance were revealed. Conclusions:We present data from 35 cases of exome sequencing applied in a setting of fetal malformations. Importantly, though, we wish to share our personal experiences with implementing WES into a prenatal setting. As a medical society, we must continue to share what we do not understand, what went wrong, what is difficult, and what we do not agree upon. A common understanding and language are warranted. We also advocate that more research is needed concerning the clinical value, as well as costs and patient perspectives, of using WES in pregnancy. We believe that WES will lead to improved prenatal and perinatal care. How to cite this article: Becher N, Andreasen L, Sandager P, et al. Implementation of exome sequencing in fetal diagnostics-Data and experiences from a tertiary center in Denmark. Acta Obstet Gynecol Scand. 2020;99:783-790.

The potential diagnostic yield of whole exome sequencing in pregnancies complicated by fetal ultrasound anomalies

“…15,21,22 Careful selection by clinical geneticist indeed results in a very high diagnostic yield. 23 Our study confirms that the potential diagnostic yield of WES in fetuses with multiple system anomalies is higher (29%, 95% CI 20.8-38.9%) than the estimated yield in the group of (isolated) single system anomalies, however the group of isolated anomalies showed a substantial percentage of abnormal cases (16.7%, 95% CI 12.6-21.8%). These results suggest that also fetuses with an isolated anomaly could be offered prenatal WES testing and confirms that patient selection based on the prenatal phenotype may be challenging.…”

“…The high diagnostic yield of Alamillo et al (42.9%), Pangalos et al (42.9%) and Vora et al (46.7%) reflects the inclusion of fetuses with multiple congenital anomalies 15,21,22 . Careful selection by clinical geneticists indeed results in a very high diagnostic yield 23 . Our study confirms that the potential diagnostic yield of WES in fetuses with multiple system anomalies is higher (29%, 95% CI 20.8%‐38.9%) than the estimated yield in the group of (isolated) single system anomalies; however, the group of isolated anomalies showed a substantial percentage of abnormal cases (16.7%, 95% CI 12.6%‐21.8%).…”

A report on the impact of rapid prenatal exome sequencing on the clinical management of 52 ongoing pregnancies: a retrospective review

“…Molecular diagnosis in cases of structural malformation allows for greater diagnostic accuracy and can have implications for management of pregnancy; whilst studies are limited in this area, decision making has reportedly been impacted in up to 70% [13][14][15][16].…”

“…12 Molecular diagnosis in cases of structural malformation allows for greater diagnostic accuracy and can have implications for management of pregnancy; although studies are limited in this area, decision making has reportedly been impacted in up to 70%. [13][14][15][16] Since 2018 we have undertaken exome sequencing in 110 cases of fetal anomaly. The work presented here focuses on those where PES was undertaken in an ongoing pregnancy and aims to quantify the added value of PES and describe the challenges of its implementation in advance of this service becoming routinely available throughout England in the near future.…”

Dealing with uncertain results from chromosomal microarray and exome sequencing in the prenatal setting: An international cross‐sectional study with healthcare professionals

“…Although uncertainty in the prenatal setting is not new, the scale and types of uncertainty that may occur is increasing because of the more detailed comprehensive analysis of the fetal genome. For example, detection of VUS has been reported in around 2%–6% of prenatal cases through CMA 2,7–9 and around 4%–20% of cases through ES, 3,10,11 although the proportion is likely to decrease as new knowledge is gained and VUS are reanalysed 11 …”