Which fetuses benefit most from exome sequencing? Results from the Prenatal Assessment of Genomes and Exomes (PAGE) study. Lyn Chitty1, Jenny Lord2, Gabriele Rinck3, Lucy Jenkins4, Richard Scott4, Ruth Eberhardt3, Dom McMullan5, Eamonn Maher6, Matthew Hurles3, On behalf of the PAGE study7
1Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health and North-East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK, London, london, United Kingdom
2The Wellcome Trust Sanger Institute, Cambridge, United Kingdom
3The Wellcome Trust Sanger Institute, Cambridge, --- Select a state ---, United Kingdom
4NE Thames Regional Genetics Laboratory, London, United Kingdom
5West Midlands Regional Genetics Service, Birmingham, United Kingdom
6Department of Medical Genetics, University of Cambridge and Cambridge NIHR Biomedical Research Centre, Cambridge, United Kingdom
7Wellcome Trust Sanger Institute, Cambridge, United Kingdom
Objectives Several small studies have shown that exome sequencing, whole exome (WES) or using a clinically focused panel, increases the diagnostic yield in structurally abnormal fetuses with a normal microarray result. Series using a multidisciplinary team, including clinical geneticists, to identify fetuses with a high likelihood of a genetic aetiology, report diagnostic rates of up to 80%. In the PAGE study we are prospectively sequencing fetus-parent trios in unselected pregnancies complicated by any fetal abnormality to determine the diagnostic yield in different categories of clinical findings. Recruitment ends in March 2018 and we will aim to report the findings to date.
Methods Parents choosing invasive testing following sonographic detection of any unexpected fetal abnormality and normal chromosomal analysis were consented for WES of excess fetal sample and parental DNA. Expert genetic or fetal medicine review was not performed. Anomalies are classified by system (Table) and, except for increased nuchal translucency, exclude minor sonographic markers. Trio WES is conducted after pregnancy and potential variants identified by analysis of targeted genes. Pathogenicity is assigned after consideration of fetal phenotypes by our clinical review panel comprising scientists, geneticists and fetal medicine specialists. Causative pathogenic variants are validated. Results explaining the phenotype are reported to parents.
Results Currently we have recruited 1318 families, of whom 783 with normal chromosomal analysis were eligible. Sequencing is ongoing with results available in 506 (Table). Overall a diagnostic genetic abnormality was identified in 41/506 cases (8∙1%) and a further 15 (3%) had a variant of uncertain significance (VUS) with potential clinical utility. Highest diagnostic yields were found in fetuses with multisystem (16%), cardiac (13.6%), and skeletal anomalies (12.5%). Diagnostic variants were only identified in two (2.1%) fetuses with isolated increased nuchal translucency (>4∙0 mm).
Conclusions The PAGE study be will complete this spring, and results to date are showing that WES with variant calling using a focused clinical panel facilitates genetic diagnosis in abnormal fetuses. The overall detection rate of 8.1% in this unselected cohort is lower than that reported by previous smaller-scale studies of cases sequenced after genetic review. Trio sequencing is likely to be needed to deliver results in a timely fashion within pregnancy. Currently this remains expensive and our large study is enabling identification of the clinical subgroups most likely to benefit from WES, thereby aiding cost-effective implementation into routine clinical practice.
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