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.

 


Biography:

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.

Clinical Genomics in the UK; more seismic changes ahead?

This talk will give an overview of the many overlapping challenges and initiatives faced by the UK NHS Clinical Genomics community as we enter the era when WGS potentially becomes a one-stop shop for many diagnostic pathways and personalised medicine becomes a reality, following investment of over £500 million in the launch of 100,000 Genomes project and the establishment of NHS Genomic Medicine Centres. The Association for Clinical Genomic Science (in many ways a “first cousin “organisation to ASDG) formed in 2012 from a merger of the Association for Clinical Cytogenetics (ACC) and the CMGS (Clinical Molecular Genetics Society), reflecting a coalescence of technology, analysis and interpretation. ACGS plays a pivotal role in guiding and inputting into key areas of service and professional development around Quality, Training as well as developments in Science and Technology and is heavily involved, as part of a constituent body of the British Society for Genomic Medicine, in initiatives and various national agendas in UK Clinical Genomics. In England, 2017 will see start of  procurement of a new genomic laboratory infrastructure, with networked Regional Genomic Central Laboratory Hubs providing routine diagnostic clinical sequencing and complex WGS analysis, the latter likely provided centrally by a national provider. A National Coordinating Centre will be established within an agreed governance and operational framework that will oversee the test repertoire and support labs to work together. This is the vision. What will it take to make it happen and how will it really work?

 


Biography: 

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.

Validation studies on a gene panel interrogating paediatric growth disorders and tumour predisposition.

Associate Professor Elizabeth Algar BSc Hons M.Phil. PhD FFSc RCPA

Principal Scientist, Genetics & Molecular Pathology, Monash Health

The Genetics and Molecular Pathology laboratory at Monash Health is the predominant Australian testing laboratory for paediatric overgrowth disorders associated with increased cancer risk in childhood, including Beckwith Wiedemann syndrome (BWS) and Hemihypertrophy (HH). Cascade testing typically involves SNP microarray, methylation analysis of imprinting centres on 11p15.5 and CDKN1C (P57) mutation screening. Rare point mutations in NSD1, NLRP2, DNMT1 and ZFP57 have been described in BWS and like disorders as well as deletions and insertions within the 11p15.5 imprinting centres IC1 (H19/IGF2) and IC2 (KCNQ1OT1/CDKN1C). Tumour risk is increased in most genetic and epigenetic subtypes of BWS and HH however degree of risk and tumour type varies between groups. Parents of affected children are often understandably anxious to know the recurrence risk for these conditions and as the number of childhood cancer survivors’ increases, the possibility for transmission of a causative mutation is becoming an increasingly important issue. To improve our capacity to detect predisposing mutations in BWS, HH and in the paediatric tumours that have been described in these conditions, we have designed a gene panel comprising 37 genes as well as intergenic regions spanning imprinting centres on 11p15.5 and 11p13. We have used the Haloplex target enrichment system with sequences run on an Illumina MiSeq. We have performed pilot testing to show that the panel has clinical utility and demonstrates excellent sequence coverage of the 11p imprinting centres. Analysis of results to date has revealed novel mutations including OCT-4 binding site disruption in IC1 and subregions of homozygosity.

About conferences.com.au

conferences.com.au provides delegate registration, website and app solutions, and financial management for conferences, conventions and scientific meetings.

Terms & Conditions

All registrations and bookings are subject to our standard term and conditions.

Contact Us

Please contact the team at conferences.com.au with any questions regarding the conference.
© 2017 - 2020 Conference Design Pty Ltd. conferences.com.au is a division of Conference Design Pty Ltd.