Evolving fetal phenotypes and the clinical impact of progressive prenatal exome sequencing pathways – a cohort study

F. Mone, H. Abu Subieh, S. Doyle, S. Hamilton, D. J. McMullan, S. Allen, T. Marton, D. Williams, M. D. Kilby

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To determine the; (i) variable diagnostic yield and turnaround time (TAT) of two consecutive prenatal exome sequencing (ES) pathways; (ii) evolution of the fetal phenotype and; (iii) clinical impact in the presence of causative pathogenic variants and incidental findings.

This retrospective cohort analysis (of prospectively collected cases) assessed fetuses undergoing trio ES in the presence of structural anomalies with normal chromosome microarray via the West Midlands Regional Genetics Laboratory. This included the periods; (a) 07/2018 to 10/2020 (a post-Prenatal Assessment of Genomes and Exomes (PAGE) pilot study) with prenatal trio ES based on a panel of 1542 development disorder genes and case selection by a multi-disciplinary team and; (b) 10/2020 to 05/2021 with prenatal trio ES based upon the NHS England R21 pathway with definitive inclusion criteria and a panel of 1205 prenatally relevant genes. Deep phenotyping was performed throughout pregnancy and postnatally.

In total n=54 cases were included. The diagnostic yields and TATs for both periods were 28% (n=7/25); 54 (14-213) days and 55.1% (n=16/29) p=0.04; 14.2 (3-29) days respectively. In instances where a causative pathogenic variant was identified, of those reaching the third trimester, additional anomalies were detected between the second and third trimesters in 73.3% (n=11) of cases, predominantly secondary to progressive hydropic features n=3 (27.3%), arthrogryposis n=3 (27.3%) and brain anomalies n=2 (18.2%). In n=3 instances, variants of uncertain significance were upgraded to likely pathogenic based upon postnatal information. Where causative pathogenic variants were detected there was a significant clinical impact in 78.3% (n=18/23), predominantly relating to decision regarding pregnancy course and potential change of neonatal management 38.9% (n=7/18).

Prenatal exome sequencing using the NHS England r21 pathway shows great promise when applied to our initial cohort, with a genetic diagnosis obtained in over half of pre-selected ultrasound detected fetal structural anomalies. Tracking and real-time updating of fetal phenotype and consideration of re-classification of variants based upon postnatal findings is vital if one is to optimise the clinical impact already evident from this emergent genomic technology.
Original languageEnglish
JournalUltrasound in Obstetrics and Gynecology
Early online date23 Dec 2021
Publication statusE-pub ahead of print - 23 Dec 2021


  • exome sequencing
  • phenotype
  • prenatal
  • ultrasound
  • pathway


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