Research in the Rare Disease Laboratory,
North Thames Genomic Laboratory Hub
The NHS North London Genomics Laboratory Hub at GOSH has a core team of researchers who are funded by the GOSH NIHR Biomedical Research Centre and various grants. The group comprises both clinical scientists, post doctoral fellows, Clinical fellows and social scientists and works at the interface of translating research into clinical practice. Current workstreams include extending diagnoses in the 100,000 Genomes project, work on developing methods of informed choice of sequencing testing both in the pre- and postnatal setting, and applying new molecular technologies to improve prenatal diagnosis of monogenic disorders. Our group is internationally renowned for translating research in prenatal diagnosis into clinical service.
Non-invasive prenatal diagnosis for monogenic disorders
For many years we have collaborated with fetal medicine and genetics units to build a sample bank of maternal and paternal blood samples that has allowed the development of non-invasive prenatal tests. The RAPID sample bank now has over 20,000 samples. We were the first laboratory internationally to introduce as accredited service for non-invasive prenatal diagnosis for fetal sex determination (2011). We then went on to introduce non-invasive prenatal diagnosis services for a range of monogenic disorders including FGFR3 related skeletal dysplasia (1,2), FGFR2-related Craniosynostosis Panel (2015), family-specific paternal and de novo mutation testing for rare conditions and cystic fibrosis (3). Since gaining UKGTN approvals for these disorders we have reported over 700 NIPD reports for monogenic disorders and over 1000 reports for fetal sex determination being one of two centres in England that now provide this testing.
Once our research team have developed the methods using samples in a sample bank, we work with the clinical service team to run the new tests on maternal blood in parallel with conventional testing to fully validate the new tests and submit them to our accrediting body for approval.
Rapid fetal exome sequencing
For the last four years, we have been involved in the evaluation of prenatal exome sequencing in the diagnostic pathway for fetuses with structural anomalies indicative of a monogenic disorder using an invasive prenatal sample (4). We developed a rapid pipeline so that results are available in around 10-14 days from receipt of the sample in the lab (5). The evidence we collected helped influence NHSE in the National Genomic Test Directory, and rapid fetal sequencing was included. The service commenced in October 2020 with GOSH being one of the two GLHs delivering the service. Following this success we are now focussed on developing methods to do this testing non-invasively.
Research to improve the diagnostic yield for the 100,000 Genomes participants
Partners in our GLH, North and West London GMCs, together recruited more than a quarter of all cases recruited to the 100,000 Genomes project, including the most cases for ophthalmology, paediatric cancer, and neurology. This is a reflection of the specialist centres that are hosted by our partners and we now have post-doctoral researchers working with our clinical scientists and BRC team to explore the missing heritability in undiagnosed cases from the 100,000 Genomes Project.
Ongoing research includes the use of third generation sequencing technology to characterise variations in regions of the genome intractable to next generation sequencing strategies
Supporting social science research
Implementation of new tests requires evaluation of the care pathways, patient and health professional views and needs, commissioner opinions and health economics to ensure equitable, appropriate implementation with appropriate costs and benefits analysis to ensure patient benefit is maximised.
The technical advances made in our laboratory are supported by social science research with parents, patients and professionals that assesses acceptability and considers issues for service delivery.
Recent research includes qualitative interviews with parents and professionals to explore their experiences of rapid genomic sequencing for critically ill children (12). The test was viewed positively and we identified challenges for informed consent and for the coordination of rapid testing.
Our mixed-methods research has examined informed decision making, experiences of testing and the impact of results from genomic sequencing offered through the 100,000 Genomes Project (5,6). As part of this we have developed information aids that are useful for children and adults alike (give links).
We are currently exploring parents’ and professionals’ experiences with prenatal exome sequencing, as well as examining how this testing is delivered by the North Thames GLH, to identify what works well and key areas for improvement. A new collaborative study, EXPRESS (Optimising EXome PRenatal Screening Services) funded by the NIHR through its NS&DR programme, will go on to look at the national implementation of prenatal exome sequencing with the aim of delivering practical recommendations that will inform the development of the new service.
Selected recent publications
- Mellis R, Chandler N, Jenkins L, Chitty LS. The role of sonographic phenotyping in delivering an efficient noninvasive prenatal diagnosis service for FGFR3-related skeletal dysplasias. Prenat Diagn. 2020 Mar 30;. doi: 10.1002/pd.5687. [Epub ahead of print] PubMed PMID: 32227640
- Jenkins L, Deans Z, Lewis C, Allen S. Delivering an accredited non-invasive prenatal diagnosis service for monogenic disorders and recommendations for best practice. Prenat Diagn. 2018 Jan;38(1):44-51 doi: 10.1002/pd.5197
- Chandler NJ, Ahlfors H, Drury S, Mellis R, Hill M, McKay FJ, Collinson C, Hayward J, Jenkins L, Chitty LS. Noninvasive Prenatal Diagnosis for Cystic Fibrosis: Implementation, Uptake, Outcome, and Implications. Clin Chem. 2019 Sep 24;. doi: 10.1373/clinchem.2019.305011. [Epub ahead of print] PubMed PMID: 31551312
- Best S, Wou K, Vora N, Van der Veyver I, Wapner R, Chitty LS. Promises, pitfalls and practicalities of prenatal whole exome sequencing. Prenat Diagn. 2018 Jan;38(1):10-19 doi: 10.1002/pd.5102
- Chandler N, Best S, Hayward J, Faravelli F, Mansour S, Kivuva E, Tapon D, Male A, DeVile C, Chitty LS. Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counselling and pregnancy management. Genet Med. 2018 Nov;20(11):1430-1437. doi: 10.1038/gim.2018.30. Epub 2018 Mar 29. PubMed PMID: 29595812
- Hay E, Hendersoin R, Mansour S, Deshpande C, Jones R, Nutan S, Mankad K, Young R, Moosajee M, Genomics England Research Consortium, Arno G. Expanding the phenotypic spectrum consequent upon de novo WDR37 missense variants. Clin Genet Aug;98(2):191-197. doi: 10.1111/cge.13795
- Bertrand R, Wang J, Xiong K, Thangavel C, Qian X, Ba-Abbad R, Liang Q,Simoes R, Sampaio S, Carss K, Raymond L, Robson A, Webster A, Arno G, Belga Ottoni Porto F, Chen R. Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy. Genet Med. 2020 doi: 10.1038/s41436-020-01003-x [Epub ahead of print]
- Schiff E, Daich Varela M, Robson A, Pierpont K, Ba-Abbad R, Nutan S, Zein W, Ullah E, Huryn L, Tuupanen S, Mahroo O, Michaelides M, Burke D, Harvey K, Arno G, Hufnagel R, Webster A. A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis. Am. J. Med Genet C. 2020 Sep;184(3):631-643 doi: 10.1002/ajmg.c.31822
- Vig A, Poulter J, Ottaviani D, Tavares E, Toropova K, Tracewska AM, Mollica A, Kang J, Kehelwathugoda O, Paton T, Maynes J, Wheway G, Arno G et al. DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration. Genet Med. 2020 Dec;22(12):2041-2051; doi: 10.1038/s41436-020-0915-1
- Khan M, Arno G, Fakin A, Parfitt D, Dhooge P, Albert S, Bax N, Duijkers L, Niblock N, Hau K, Bioch E, Schiff E, Piccola D, Hogden M, Hoyng C, Webster A, Cremers F, Cheetham M, Garanto A, Collin R. Mol Ther Nucleic Acids 2020 Sep 4;21:412-427 doi: 10.1016/j.omtn.2020.06.007
- Turro E et al Whole-genome sequencing of patients with rare diseases in a national health system. Nature 2020 Jul;583(7814):96-102doi: 10.1038/s41586-020-2434-2.
- Hill M, Hammond J, Lewis C, Mellis R, Clement E, Chitty LS. Delivering genome sequencing for rapid genetic diagnosis in critically ill children: parent and professional views, experiences and challenges. Eur J Hum Gen 2020;28(11):1529-40
- Sanderson SC, Hill M, Patch C, Searle B, Lewis C, Chitty LS. Delivering genome sequencing in clinical practice: an interview study with healthcare professionals involved in the 100 000 Genomes Project. BMJ Open. 2019;9(11):e029699
- Lewis C, Sanderson S, Hill M, Patch C, Searle B, Hunter A, et al. Parents’ motivations, concerns and understanding of genome sequencing: a qualitative interview study. European journal of human genetics : EJHG. 2020;28(7):874-84
Current and recent grants (*GOSH lead partner)
- 2017-22: *GOSH NIHR Biomedical Research Centre funding
- 2020-23: *NIHR HS&DR. EXPRESS – Evaluation of prenatal exome sequencing – £1,325,000
- 2016-21: EU H2020. BOOST B4 (Boost Brittle Bones Before Birth) – total award €6,608,754.75
- 2016-18: *AMR & GOSHCC Developing non-invasive prenatal diagnosis for autosomal recessive conditions: cystic fibrosis and spinal muscular atrophy – £198,634
- 2016-20: *RfPB, NIHR. Defining patient priorities for whole genome sequencing – £344,067
- 2014-18: HICF. Prenatal assessment of genomes and exomes (PAGE) – £4,062,337
- 2008-15: *NIHR PGfAR. Reliable accurate prenatal
non-invasive diagnosis (RAPID) – £2,325,006