Update on the use of exome sequencing in the diagnosis of fetal abnormalities

Abstract

Unexpected fetal abnormalities detected through ultrasound scanning in pregnancy may have a monogenic aetiology but are difficult to diagnose. Next generation sequencing now enables us to sequence fetal exomes, providing increased resolution and broader diagnostic capability compared to traditional cytogenetic prenatal tests, improving the yield and accuracy of diagnoses and allowing better counselling for expectant parents. Here we review published studies of exome sequencing (ES) for prenatal diagnosis over the last 5 years and address important questions for its clinical implementation, including clinical utility, which groups benefit most, and practical and ethical challenges for interpreting and reporting results. We observe that fetal ES substantially improves diagnostic yield relative to cytogenetic techniques. However, diagnostic rates vary widely between studies, largely attributable to differences in case selection. Recently several large studies report variations in diagnostic yield between phenotypic groups, with fetuses with multisystem abnormalities most likely to receive a diagnosis from fetal ES. Challenges for prenatal ES include the limitations of ultrasound-based fetal phenotyping, the need for rapid return of results in pregnancy, and technical limitations compared to whole genome sequencing. We also consider ethical issues around potential secondary findings and variants of uncertain significance and the complex counselling needs these present. Prenatal ES is a valuable tool to diagnose fetal abnormalities and, as it is implemented in the clinic, more large-scale research will serve to further delineate its clinical utility, as well as

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

“…There were significant findings in ongoing pregnancies, in fetal tissue from previous pregnancies and in all 3 trimesters. As also described in other studies, 10,11,15 the diagnostic yield was highest among the multisystem‐affected fetuses.…”

“…We have mainly experienced how WES provided couples with informed reproductive choices enabling compassionate care of the newborn. Parents express a better coping with the situation when knowing the diagnosis of the child 15,18 . We have also experienced that a normal result of WES caused some relief in the light of a decreased risk of many severe diagnoses.…”

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“…The fetus presented with agenesis of the corpus callosum and bilateral syndactyly of the hands and feet but no sign of craniosynostosis, which is a hallmark feature of Apert syndrome. Ferretti et al described a similar situation where a fetus with poor intrauterine growth and a pathogenic missense variant in NSD1 only demonstrated classic signs of Sotos syndrome at 1 year of age . Similarly, autosomal dominant mutations in RERE are associated with a neurodevelopmental disorder with or without anomalies of the brain, eye, or heart.…”

Dual independent genetic etiologies in a lethal complex malformation phenotype

“…Great potential is expected from novel next generation sequencing approaches allowing the mole- cular analysis of all coding and disease-relevant genes, the so-called clinical exome, in a comparably short time span, now entering prenatal medicine. Recent studies report an additional diagnosis in up to 10 % for prenatal mixed clinical indications [5,6], and in up to 20-60 % of cases in smaller but clinically well-defined and selected cohorts, particularly in the presence of multiple anomalies [7]. The most important challenge, however, is the interpretation of the large amount of sequence variants most of which are not described to date.…”