Prenatal Exome Sequencing Analysis in Fetal Structural Anomalies Detected by Ultrasonography (PAGE): A Cohort Study

摘要

Fetal structural anomalies, detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs), and pathogenic sequence variants in developmental genes. Conventional prenatal cytogenetic analysis was historically the first-line method to investigate these anomalies, but chromosomal microarray analysis has been adopted more recently, as this test is able to detect smaller, but significant, CNVs. There is interest in genome-wide sequencing to investigate prenatally detected congenital abnormalities, including whole-genome sequencing and whole-exome sequencing (WES), although until now limited data have existed to determine clinical usefulness of these analyses in this setting. The researchers sought to evaluate the proportion of fetuses with structural abnormalities that had identifiable gene variants associated with developmental disorders when assessed with WES. The researchers performed a prospective cohort study of patients recruited from 34 fetal medicine units in England and Scotland. The researchers used WES to evaluate the presence of genetic variants in developmental disorder genes in a cohort of fetuses with structural anomalies. Inclusion criteria for the study were women who were undergoing invasive testing for identified enlarged nuchal translucency or structural anomalies in their fetus after 11 weeks of gestation. The primary end point was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analyzed as 596 fetus-parental trios, including 2 sets of twins, and 14 fetus-parent dyads) were analyzed by WES. After bioinformatics filtering and prioritization according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic (diagnostic genetic variants). A diagnostic genetic variant was identified in 52 (8.5%; 95% confidence interval, 6.4-11.0) of 610 fetuses assessed, and an additional 24 fetuses (3.9%) had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled the investigators to distinguish between syndromic and nonsyndromic fetal anomalies (eg, isolated congenital heart disease vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15.4%) of 143 fetuses with multisystem anomalies (ie, > 1 fetal structural anomaly), 9 (11.1%) of 81 fetuses with cardiac anomalies, and 10 (15.4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. Diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (>4.0 mm) in the first trimester (3 [3.2%] of 93 fetuses). The researchers found that the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. However, using WES substantially increased the number of fetuses that could be diagnosed with genetic variants associated with developmental disorder genes and improved the prognostic information that could be provided for the current and future pregnancies (such as recurrence risks). The researchers do note that more data will be needed to determine whether whole-genome sequencing is superior to chromosomal microarray and WES.