Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography: the PAGE study

Research output: Contribution to journalArticle


  • Jenny Lord
  • Dominic McMullan
  • Ruth Y Eberhardt
  • Gabriele Rinck
  • Sue Hamilton
  • Elizabeth Quinlan-Jones
  • Elena Prigmore
  • Rebecca Keelagher
  • Sunayna K Best
  • Georgina K Carey
  • Ian R Berry
  • Kate E Chandler
  • Lara Cresswell
  • Sandra L Edwards
  • Alex Henderson
  • Simon T Holden
  • Tessa Homfrey
  • Rebecca Lewis
  • Ruth Newbury-Ecob
  • Katrina Prescott
  • Oliver Quarrell
  • Simon Ramsden
  • Eileen Roberts
  • Dagmar Tapon
  • Madeleine J Tooley
  • Pradeep C Vasudevan
  • Astrid P Weber
  • Diana G Wellesley
  • Paul Westwood
  • Helen White
  • Michael Parker
  • Denise Williams
  • Lucy Jenkins
  • Richard H Scott
  • Lynn Chitty
  • Matthew E Hurles
  • Prenatal Assessment of Genomes and Exomes Study

External organisations

  • Wellcome Trust Sanger Inst
  • West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
  • UCL
  • Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester, M13 9WL
  • University Hospitals of Leicester NHSTrust
  • UCL
  • Department of Clinical Genetics, Birmingham Women's Hospital NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham, B15 2TG


Background: Fetal structural anomalies (FSA) detected by ultrasonography have a range of genetic aetiologies including chromosomal aneuploidy, copy number variations (CNVs) detectable by chromosomal microarrays (CMA) and pathogenic sequence variants in developmental genes. Investigations to detect aneuploidy and CNVs are routinely used for the investigation of FSA but information on the clinical utility of genome-wide next generation sequencing in the prenatal setting is limited. Methods: Whole exome sequencing (WES) was performed, after exclusion of aneuploidy and large CNVs, on a prospective cohort of 392 fetuses with FSA and in 772 parental samples (380 case-parental trios and 12 case-parent dyads). Sequencing was interpreted based on a targeted developmental disorder virtual gene panel comprising 1536 genes. Genetic results relevant to the phenotype were validated and reported after the pregnancy was completed. Findings: After bioinformatic filtering and prioritisation, 201 genetic variants representing 155 potential diagnoses were selected as “potential pathogenic variants” and reviewed by a multidisciplinary clinical review panel (CRP). A diagnostic genetic abnormality was identified in 34/392 cases (8∙7%;95%CI:6∙1-11∙9%) and a further 12(3∙1%) had a variant of uncertain significance (VUS) with potential clinical utility. Variant detection enabled syndromic and non-syndromic cases of fetal anomaly to be distinguished. Diagnostic variants were more common in fetuses with multisystem anomalies (more than one FSA) (16∙9%(13/77)), cardiac anomalies (18∙4%,(9/49)), skeletal anomalies (15∙4%,(6/39)) and hydrops fetalis (10∙5%,(2/19)) and less frequent in fetuses with isolated increased nuchal translucency (>4∙0 mm) in the first trimester (1∙1%, (1/88)). Interpretation: WES facilitates genetic diagnosis in FSAs enabling more accurate prediction of fetal prognosis and risk of recurrence in future pregnancies. However the overall detection rate in a prospectively ascertained, unselected cohort is lower than that suggested by previous smaller-scale studies of highly selected phenotypes.


Original languageEnglish
Pages (from-to)747-757
JournalThe Lancet
Issue number10173
Early online date31 Jan 2019
Publication statusPublished - 1 Mar 2019