Exome sequencing of 406 parental/fetal trios with structural abnormalities revealed by ultrasound in the UK Prenatal Assessment of Genomes and Exomes (PAGE) project

D. J. McMullan1, J. Lord2, R. Eberhardt2, G. Rinck2, S. Hamilton1, R. Keelagher1, L. Jenkins3, E. Quinlan-Jones4, D. Williams5, R. Scott6, M. Kilby4,7, L. Chitty6, E. Maher8, M. Hurles2;

1West Midlands Regional Genetics Laboratory, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom, 
2The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom,
3NE Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London, United Kingdom, 
4Department of Fetal Medicine, Birmingham Women’s and Children’s Hospital, Birmingham, United Kingdom, 
5West Midlands Clinical Genetics Service, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom, 
6Genetics and Genomic Medicine, UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom, 
7Centre for Women’s and New-born Health, IMSR, University of Birmingham, Birmingham, United Kingdom, 
8Department of Medical Genetics, University of Cambridge and Cambridge NIHR Biomedical Research Centre, Cambridge, United Kingdom.

PAGE aims to apply whole exome sequencing (WES) to 1000 trios recruited in the UK-NHS over 3 years to identify pathogenic variation underlying heterogeneous fetal structural abnormalities detected by ultrasound scan (USS).

Trio WES is conducted only after resolution of pregnancy if conventional testing (QF-PCR, chromosomal microarray or targeted single/panel gene testing) fails to establish a definitive diagnosis. Genetic variants are triaged via a stringent filtering pipeline established for the UK Deciphering Developmental Disorders (DDD) project and potentially pathogenic variants are assessed and classified by a UK-wide multidisciplinary clinical review panel (CRP), technically validated in NHS accredited labs and reported back to Clinical Genetics units and families where appropriate. Thus far from 259 trios reviewed by the CRP, 16 likely diagnoses have been revealed, giving a diagnostic yield of ~6%. Diagnostic yield varies by phenotypic class, with multisystem phenotypes showing the highest (~16%). The majority of variants are SNVs/indels which would escape targeted detection by conventional testing. When compared to a null model based on triplet mutation rate, an excess of de novo mutation is observed, more pronounced in known dominant genes (such as KMT2D). Further analysis is predicted to identify new gene and mechanistic associations underlying observed phenotypes as more samples are processed. PAGE aims to catalyse responsible adoption of WES and potentially WGS in routine diagnostics in the prenatal setting and this talk will outline all aspects of this multidisciplinary and multifaceted project.



Dom McMullan is a Consultant Registered Clinical Scientist at West Midlands Regional Genetics Laboratories, Birmingham, United Kingdom, with 25 years’ experience in all aspects of diagnostic / clinical laboratory genetics. He graduated from the University of Sheffield in Genetics and is a Fellow of the Royal College of Pathologists (Genetics). He leads the Germline Programme of the laboratory service, which encapsulates all rare disease and reproductive genetic testing serving a patient population of ~5.5 million. He is current Chair of the Scientific Subcommittee of the Association of Clinical Genetic Science (ACGS) and Chair of the Scientific Programme Committee for the British Society of Genetic Medicine (BSGM) annual conference. His main interests lie broadly in application of genomic technologies in detection and interpretation of structural and sequence variation; in particular in patients with developmental disorders/congenital anomalies both in the postnatal and prenatal settings and he is co-applicant/collaborator and WMRGL lead on the UK National Health Innovation Challenge Fund (HICF) Prenatal Assessment of Genomes and Exomes (PAGE) project. A strong advocate of the need for improved data-sharing between UK-NHS diagnostic laboratories (and further) he is involved in several initiatives around this with both DECIPHER and the PHG Foundation. He has been involved internationally with the ClinGen (formerly ISCA) consortium as a member of the Gene Dosage Curation working group and as an assessor on multiple UK National External Quality Assessment Schemes (NEQAS) in genetic testing.

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