Evolving fetal phenotypes and clinical impact of progressive prenatal exome sequencing pathways: cohort study

Abstract

What are the novel findings of this work?In this preliminary cohort study, the National Health Service (NHS) England R21 prenatal exome sequencing pathway provided a unifying genetic diagnosis in over 50% of preselected cases with a structural anomaly on prenatal ultrasound. What are the clinical implications of this work?Prenatal exome sequencing using the NHS England R21 pathway can provide diagnostic information in fetuses with a structural malformation. It is important to monitor fetal phenotype throughout the pregnancy and re-evaluate the phenotype postnatally when interpreting prenatal exome sequencing findings to optimize the clinical impact that is already evident from this emerging genomic technology.

Reply

“…We thank Drs Li and Li for their comments on our recent study 1 . Our paper highlights the challenges of introducing a prenatal exome sequencing (ES) service into a clinical pathway within the National Health Service (NHS) in England and demonstrates that pretest multidisciplinary discussion within a designated fetal medicine/genetics clinic and sequential ultrasound scans to define the fetal phenotype lead to optimal clinical utility.…”

Ongoing reanalysis of prenatal exome sequencing data leads to higher diagnostic yield

“…Mone et al . reported that ES had a significant clinical impact in 78.3% (18/23) of cases in which a causative pathogenic variant was detected 5 . Why did the test results have no clinical impact in 21.7% (5/23) of patients and what were the ES results of these patients?…”

“…Mone et al . recently reported their initial experience in the application of R21 pathway 5 . Of the 54 included cases, 25 underwent prenatal trio ES following selection by a multidisciplinary team (pre‐R21) and 29 had prenatal trio ES based on the NHS England R21 pathway, with deep phenotyping performed throughout pregnancy and postnatally.…”

“…uk/publication/nationalgenomic-test-directories/), which includes rapid prenatal exome sequencing (R21) in ongoing pregnancies with multisystem major structural and selected isolated fetal anomalies. Mone et al recently reported their initial experience in the application of R21 pathway 5 . Of the 54 included cases, 25 underwent prenatal trio ES following selection by a multidisciplinary team (pre-R21) and 29 had prenatal trio ES based on the NHS England R21 pathway, with deep phenotyping performed throughout pregnancy and postnatally.…”

Next Generation Sequencing after Invasive Prenatal Testing in Fetuses with Congenital Malformations: Prenatal or Neonatal Investigation

“…Clinical diagnostic yield was relatively low at 10–12% overall. Selection of cases using a ‘pre-test’ multidisciplinary team (including a Clinical Geneticist) and careful ‘targeting’ of specific fetal phenotypes may significantly increase diagnostic rate to over 30% [ 4 , 5 , 6 ].…”