ArticleThe New England journal of medicine2023
Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland.
Open access · bronzeAbstract readMulticenter Study
In one paragraph
Article in The New England journal of medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 130 papers, 1 of them a synthesis that pooled it.
0numbers the graph read from it
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130citing papers in PubMed, 1 pooled it
65.1field-weighted citation impact, top 1% of its field
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Who cites it
130 citing papers in PubMed, 1 synthesis or guideline pooled it, 209 citations in OpenAlex.
- Genetic insights into human cortical organization and development through genome-wide analyses of 2,347 neuroimaging phenotypes.Nature genetics · 2023Pooled it
- A nationwide prospective randomized trial for diagnosing developmental disorders demonstrates genome sequencing outperforms standard of care.Genome medicine · 2026Trial
- Detecting pathogenic structural variation in families with undiagnosed rare disease in a national genome project.European journal of human genetics : EJHG · 2026Article
- Caring for Rare Genetic Disease: A Vision for the Future.Journal of genetic counseling · 2026Article
- Global recommendations for the use of diagnostic genomic sequencing in the prenatal setting on behalf of the ESHG and ISPD.European journal of human genetics : EJHG · 2026Article
- Review
- Obtaining a Diagnostic Yield via Scan findings prior to the introduction of SEquencing retrospectivelY (ODYSSEY): a cohort study.Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology · 2026Article
- T-rex: standardized analysis of germline variants in whole-exome sequencing trios.Scientific reports · 2026Article
- Diagnostic delay, care needs, and trust in healthcare among persons with rare disease and their next of kin living in Sweden.Journal of community genetics · 2026Article
- Genome sequencing reveals high diagnostic yield in children with severe sporadic developmental language disorder.European journal of human genetics : EJHG · 2026Article
- Automated reanalysis of genomic data for rare disease diagnostics at scale.Nature medicine · 2026Article
- Best practice recommendations for bioinformatics approaches applied to high-throughput sequencing for rare disease and cancer diagnosis within the UK National Health Service.Journal of medical genetics · 2026Article
- Copy number variant analysis by exome sequencing is an effective approach to optimize diagnostic yield for developmental disorders-the DDD-Africa study.European journal of human genetics : EJHG · 2026Article
- Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency.Science advances · 2026Article
- AVITI sequencing of a four-generation CEPH/Utah pedigree confirms low mutation rates at homopolymer loci despite their low sequence complexity.Genome biology · 2026Article
- Population Prevalence, Penetrance, and Mortality for Genetically Confirmed MODY.The Journal of clinical endocrinology and metabolism · 2026Article
- Determinants of DNA-sequence-based Diagnostic Yield in the CSER Consortium.medRxiv : the preprint server for health sciences · 2026Article
- Genetic confounding in the associations between maternal health and autism.medRxiv : the preprint server for health sciences · 2026Article
- Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy.Nature genetics · 2026Article
- Deleterious coding variation associated with autism is shared across ancestries.Nature medicine · 2026Article
70 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
23 authors at 3 institutions in 1 country.
Caroline F WrightFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.ORCID 0000-0003-2958-5076
Patrick CampbellFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Ruth Y EberhardtFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Stuart AitkenFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Daniel PerrettFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Simon BrentFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Petr DanecekFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Eugene J GardnerFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
V Kartik ChundruFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Sarah J LindsayFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.ORCID 0000-0002-0965-3070
Katrina AndrewsFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Juliet HampsteadFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Joanna KaplanisFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Kaitlin E SamochaFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Anna MiddletonFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Julia ForemanFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Rachel J HobsonFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.ORCID 0000-0003-1997-9557
Michael J ParkerFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Hilary C MartinFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
David R FitzPatrickFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.ORCID 0000-0003-4861-969X
Matthew E HurlesFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
Helen V FirthFrom the Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter (C.F.W.), the Wellcome Sanger Institute (P.C., R.Y.E., D.P., S.B., P.D., E.J.G., V.K.C., S.J.L., K.A., J.H., J.K., K.E.S., J.F., R.J.H., H.C.M., M.E.H., H.V.F.), European Molecular Biology Laboratory, European Bioinformatics Institute (D.P., S.B., J.F.), and Wellcome Connecting Science (A.M.), Wellcome Genome Campus, and Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital (P.C., H.V.F.), Cambridge, the Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (S.A., D.R.F.), and the Wellcome Centre for Ethics and Humanities, Ethox Centre, Oxford Population Health, Big Data Institute, University of Oxford, Oxford (M.J.P.) - all in the United Kingdom.
DDD Study
Royal Devon and Exeter Hospital · GBEuropean Bioinformatics Institute · GBUniversity of Exeter · GB
Funding
Health Innovation Challenge FundMedical Research Council MC_UU_00007/3Wellcome Trust 223718
Abstract
backgroundPediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits.
methodsWe conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis.
resultsA total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent-offspring trio and 2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we made a diagnosis in approximately 41% of probands (5502 of 13,449). Of 3599 probands in trios who received a diagnosis by clinical assertion, approximately 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent-offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks' gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78).
conclusionsAmong probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.).
Indexed as
GenomicsRare DiseasesChildChild Behavior DisordersCongenital AbnormalitiesExomeFaciesGenetic Association StudiesGenetic Diseases, InbornGrowth DisordersHumansIrelandNeurodevelopmental DisordersOligonucleotide Array Sequence AnalysisUnited Kingdom
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.