dc.contributor.author | Wright, CF | |
dc.contributor.author | McRae, JF | |
dc.contributor.author | Clayton, S | |
dc.contributor.author | Gallone, G | |
dc.contributor.author | Aitken, S | |
dc.contributor.author | FitzGerald, TW | |
dc.contributor.author | Jones, P | |
dc.contributor.author | Prigmore, E | |
dc.contributor.author | Rajan, D | |
dc.contributor.author | Lord, J | |
dc.contributor.author | Sifrim, A | |
dc.contributor.author | Kelsell, R | |
dc.contributor.author | Parker, MJ | |
dc.contributor.author | Barrett, JC | |
dc.contributor.author | Hurles, ME | |
dc.contributor.author | FitzPatrick, DR | |
dc.contributor.author | Firth, HV | |
dc.date.accessioned | 2018-04-09T12:25:12Z | |
dc.date.issued | 2018-01-11 | |
dc.description.abstract | PurposeGiven the rapid pace of discovery in rare disease genomics, it is likely that improvements in diagnostic yield can be made by systematically reanalyzing previously generated genomic sequence data in light of new knowledge.MethodsWe tested this hypothesis in the United Kingdom-wide Deciphering Developmental Disorders study, where in 2014 we reported a diagnostic yield of 27% through whole-exome sequencing of 1,133 children with severe developmental disorders and their parents. We reanalyzed existing data using improved variant calling methodologies, novel variant detection algorithms, updated variant annotation, evidence-based filtering strategies, and newly discovered disease-associated genes.ResultsWe are now able to diagnose an additional 182 individuals, taking our overall diagnostic yield to 454/1,133 (40%), and another 43 (4%) have a finding of uncertain clinical significance. The majority of these new diagnoses are due to novel developmental disorder-associated genes discovered since our original publication.ConclusionThis study highlights the importance of coupling large-scale research with clinical practice, and of discussing the possibility of iterative reanalysis and recontact with patients and health professionals at an early stage. We estimate that implementing parent-offspring whole-exome sequencing as a first-line diagnostic test for developmental disorders would diagnose >50% of patients. | en_GB |
dc.description.sponsorship | The DDD study presents independent research commissioned by
the Health Innovation Challenge Fund (grant HICF-1009-003), a
parallel funding partnership between the Wellcome Trust and the
Department of Health, and the Wellcome Trust Sanger Institute
(grant WT098051). H.V.F. is supported by the Wellcome Trust
(award 200990/Z/16/Z;) “Designing, developing and delivering
integrated foundations for genomic medicine”). The research
team acknowledges the support of the National Institute for
Health Research, through the Comprehensive Clinical Research
Network. | en_GB |
dc.identifier.citation | Awaiting citation | en_GB |
dc.identifier.doi | 10.1038/gim.2017.246 | |
dc.identifier.uri | http://hdl.handle.net/10871/32393 | |
dc.language.iso | en | en_GB |
dc.publisher | Nature Publishing Group | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/29323667 | en_GB |
dc.rights | © The Author(s) 2018. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ | en_GB |
dc.subject | Diagnostic yield | en_GB |
dc.subject | Exome sequencing | en_GB |
dc.subject | Reanalysis | en_GB |
dc.subject | Reclassification | en_GB |
dc.subject | Recontact | en_GB |
dc.title | Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders. | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2018-04-09T12:25:12Z | |
dc.identifier.issn | 1098-3600 | |
exeter.place-of-publication | United States | en_GB |
dc.description | This is the final version of the article. Available from Nature via the DOI in this record. | en_GB |
dc.identifier.journal | Genetics in Medicine | en_GB |