Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study

Abstract

Summary Background Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). Methods In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. Findings The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4–11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart dis...

Fetal phenotypes emerge as genetic technologies become robust

“…As an initial commentary, however, these cases underscore potential areas of future research including the biology behind the discordance of fetal and newborn/childhood phenotypes, and the challenges to dysmorphology‐based imaging. As a limited series, the counseling burden associated with variants of unknown significance was not addressed but is an additional area for ongoing assessment . Curation of fetal genetic variants will depend on close communication between the clinicians and testing laboratories to assist with the understanding of not only the known pathogenic variants but also those with less robust information.…”

“…When an ultrasound abnormality is identified, chromosome microarray (CMA) is now the first‐line test . Following a normal CMA, specific gene panels and sequencing, both exome and whole genome, are often considered given data showing an improved diagnostic yield in anomalous fetuses . The combined advances in both genetic investigations and imaging are uncovering fetal phenotypes atypical from those classically associated with a newborn, child, or adult with the same genetic condition.…”

Prenatally diagnosed developmental abnormalities of the central nervous system and genetic syndromes: A practical review

“…The disadvantages are that panel content may not be up to date with the newest disease gene discoveries because they are typically developed on the basis of information on disease genes for conditions that present after birth and not optimized for prenatal presentations. A potentially more successful strategy that we favor is genome‐wide sequencing, such as diagnostic exome sequencing, which has already shown benefit for prenatal cases with CNS abnormalities, but full investigation of the clinical utility and their place in prenatal genetic testing is still underway …”

A system‐based approach to the genetic etiologies of non‐immune hydrops fetalis

“…In cohorts of all prenatal anomalies, WES has demonstrated a clear or likely diagnostic yield in 9% to 47% of cases when microarray and/or karyotype are normal . A recently published large prospective cohort study demonstrated a yield of 8.5% for diagnostic genetic variants in fetuses with a variety of structural anomalies, and the diagnostic yield specifically for the NIHF cases within this cohort was 9%. Finally, among a cohort of deceased fetuses with anomalies undergoing WES, 41% of cases with pathogenic variants, and 31% of cases with variants in candidate genes had hydrops …”