Prenatal exome sequencing and impact on perinatal outcome: cohort study | Poljak B, et al | Ultrasound in Obstetrics & Gynecology | Mar. 2023

Abstract

Primarily to determine the uptake of prenatal exome sequencing (pES) and diagnostic yield of pathogenic (causative) variants in a UK tertiary Fetal Medicine Unit following the introduction of the R21 NHS England pathway. Secondly, to identify how the decision to proceed with pES and identification of causative variants affect perinatal outcomes, specifically late termination of pregnancy (TOP) at or beyond 22 weeks’ gestation.

Retrospective cohort study of anomalous fetuses 01/03/21-28/02/22 referred to the Liverpool Women's Hospital Fetal Medicine Unit. All pES were performed as part of the R21 NHS England pathway. Trio exome sequencing was performed using an Illumina NGS platform assessing coding and splice regions of a panel of n=974 prenatally relevant genes and n=231 expert reviewed genes. Demographics, phenotype, pES result and perinatal outcome were extracted. Descriptive statistics and chi square tests were performed with IBM SPSS version 28.0.1.0.

n=72 cases were identified, two thirds of eligible women (n=48) consented to trio pES. pES was not feasible in one case due to low DNA yield, and n=47 pES were completed. In a third of cases (n=24) pES was not proposed, in 58% (n=14) this was because invasive testing was declined. In 42% (n=10) women opted for testing and had chromosome microarray only. The diagnostic yield of pES was 23% (n=11/47). There was no overall difference in decisions for late TOP where pES was agreed and where pES was not proposed (25% (n=12/48) vs 25% (n=6/24), p=1.0). However late TOP was significantly more frequent when a causative variant was detected compared to when pES was non-informative (63.6% (n=7/11) vs 13.8% (n=5/36), p<0.0009). The median turnaround time for results was longer where a causative variant was identified than for those where pES was non-informative (22 days (interquartile range (IQR), 19-34) days vs 14 days (IQR, 10-15 days); p≤0.0001).

This study demonstrates the potential impact of causative variants identified by pES on decisions for late TOP. As the R21 pathway continues to evolve we urge clinicians and policymakers to consider earlier screening for anomalies, develop robust guidance for late TOP and ensure optimized support for couples.