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

Abstract

The aim of this retrospective cohort study was to determine the potential diagnostic yield of prenatal whole exome sequencing in fetuses with structural anomalies on expert ultrasound scans and normal chromosomal microarray results. Material and methods: In the period 2013-2016 391 pregnant women with fetal ultrasound anomalies who received normal microarray results, were referred for additional genetic counseling and opted for additional molecular testing pre-and/or postnatally. Most of the couples received only a targeted molecular test and in 159 cases (40.7%) whole exome sequencing (broad gene panels or open exome) was performed. The results of these molecular tests were evaluated retrospectively, regardless of the time of the genetic diagnosis (pre-or postnatal). Results: In 76 of 391 fetuses (19.4%, 95% CI 15.8-23.6%) molecular testing provided a genetic diagnosis with identification of (likely) pathogenic variants. In the majority of cases (91.1%, (73/76) the (likely) pathogenic variant would be detected by prenatal whole exome sequencing analysis. Conclusions: Our retrospective cohort study shows that prenatal whole exome sequencing, if offered by a clinical geneticist, in addition to chromosomal microarray, would notably increase the diagnostic yield in fetuses with ultrasound anomalies and would allow early diagnosis of a genetic disorder irrespective of the (incomplete) fetal phenotype.

Fetal phenotypes of Mendelian disorders: A descriptive study from India

“…Skeletal dysplasias and dysmorphic syndromes were the largest disease categories in this series. Although specific proportions are not indicated, other large case series also show dysmorphic syndromes and skeletal dysplasias as the leading diagnostic groups 3,4,8,14,40 . Ciliopathies were the largest molecular diagnostic group seen in 15% cases in this study.…”

Diagnostic yield of exome sequencing in fetuses with multisystem malformations: systematic review and meta‐analysis

“…In relation to the diagnostic yield of individual anatomical systems involved in cases with multisystem anomalies, the highest yields were observed for craniofacial dysmorphism (47% of fetuses with this anomaly were positive on ES), central nervous system anomalies (45%) and musculoskeletal anomalies (43%), while the lowest yields were for fetal hydrops (19%) and gastrointestinal anomalies (27%) (Figure 4 and Table S1). Among the 17 selected studies, only three reported data on incidental findings 22,31,32 , resulting in a frequency ranging from 1.1% to 6.1%, while four reported on secondary findings 4,26,27,29 , with a frequency ranging from 3.9% to 21%.…”

Prenatal exome sequencing: A useful tool for the fetal neurologist

“…Most pathogenic or likely pathogenic mutations were inherited in an autosomal recessive way (60%). This diagnostic yield might be biased due to our small sample size, as it is higher than in previous studies containing fetuses with a variety of malformations on prenatal US (8.5-19.4% 8,18,19 ) and in our previous study, excluding the neurological cases that were included in this report (17% 11 ). Our diagnostic yield is comparable with previous publications investigating pES in a selected cohort of fetuses with CNS malformations.…”

“…When a result of CMA could not be obtained before 22 + 0 weeks of gestation and parents considered TOP, pES was initiated simultaneously. Cases 1,2,5,8,12,16,17,and 19 were also included in our previous study. 11 We adhered to our previously formulated definition of clinical impact, 11 being;…”