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dc.contributor.authorWright, CF
dc.contributor.authorCampbell, P
dc.contributor.authorEberhardt, RY
dc.contributor.authorAitken, S
dc.contributor.authorPerrett, D
dc.contributor.authorBrent, S
dc.contributor.authorDanacek, P
dc.contributor.authorGardner, EJ
dc.contributor.authorChundru, VK
dc.contributor.authorLindsay, SJ
dc.contributor.authorAndrews, K
dc.contributor.authorHampstead, J
dc.contributor.authorKaplanis, J
dc.contributor.authorSamocha, KE
dc.contributor.authorMiddleton, A
dc.contributor.authorForeman, J
dc.contributor.authorHobson, RJ
dc.contributor.authorParker, MJ
dc.contributor.authorMartin, HC
dc.contributor.authorFitzPatrick, DR
dc.contributor.authorHurles, ME
dc.contributor.authorFirth, HV
dc.date.accessioned2023-03-03T09:49:19Z
dc.date.issued2023-04-12
dc.date.updated2023-03-03T07:54:58Z
dc.description.abstractBackground: Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genome-wide diagnostic approaches. Finding a molecular diagnosis is challenging but can have lifelong benefits. Methods: The Deciphering Developmental Disorders (DDD) study recruited >13,500 families with severe, likely monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services around the UK and Ireland. We collected standardised phenotype data and performed exome sequencing and microarray analysis to investigate novel genetic causes. We developed an iterative variant analysis pipeline, reporting candidate variants to clinical teams for validation, diagnostic interpretation and communication to families. We performed multiple regression analyses evaluating factors affecting probability of diagnosis. Results: We reported ~1 candidate variant per parent-offspring trio and ~2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we achieved a diagnosis in ~41% (5502 probands), of whom ~76% have a pathogenic de novo variant. Another ~22% have variants of uncertain significance in genes robustly linked with monogenic developmental disorders. Recruitment as a parent-offspring trio had the largest impact on chance of diagnosis (OR=4.70). Probands who were extremely premature (OR=0.39), had in-utero exposure to antiepileptic medications (OR=0.44), or whose mothers had diabetes (OR=0.52) were less likely to be diagnosed, as were those of African ancestry (OR=0.51). Conclusions: The DDD study shows multimodal analysis of genome-wide data has good diagnostic power, even after prior attempts at diagnosis.en_GB
dc.description.sponsorshipHealth Innovation Challenge Funden_GB
dc.description.sponsorshipWellcome Sanger Instituteen_GB
dc.description.sponsorshipWellcome Trusten_GB
dc.identifier.citationPublished online 12 April 2023en_GB
dc.identifier.doi10.1056/NEJMoa2209046
dc.identifier.grantnumberHICF-1009-003en_GB
dc.identifier.grantnumberWT098051en_GB
dc.identifier.grantnumberWT223718/Z/21/Zen_GB
dc.identifier.urihttp://hdl.handle.net/10871/132594
dc.identifierORCID: 0000-0003-2958-5076 (Wright, Caroline)
dc.language.isoen_USen_GB
dc.publisherMassachusetts Medical Societyen_GB
dc.rights© 2023 Massachusetts Medical Society. This version is made available under the CC-BY 4.0 license: https://creativecommons.org/licenses/by/4.0/
dc.subjectgenomic medicineen_GB
dc.subjectrare diseaseen_GB
dc.titleGenomic diagnosis of rare pediatric disease in the United Kingdom and Irelanden_GB
dc.typeArticleen_GB
dc.date.available2023-03-03T09:49:19Z
dc.identifier.issn0028-4793
dc.descriptionThis is the author accepted manuscript. The final version is available from the Massachusetts Medical Society via the DOI in this recorden_GB
dc.identifier.eissn1533-4406
dc.identifier.journalNew England Journal of Medicineen_GB
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_GB
dcterms.dateAccepted2023-01-24
dcterms.dateSubmitted2022-07-04
rioxxterms.versionAMen_GB
rioxxterms.licenseref.startdate2023-01-24
rioxxterms.typeJournal Article/Reviewen_GB
refterms.dateFCD2023-03-03T07:55:00Z
refterms.versionFCDAM
refterms.dateFOA2023-04-24T15:18:38Z
refterms.panelAen_GB


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© 2023 Massachusetts Medical Society. This version is made available under the CC-BY 4.0 license: https://creativecommons.org/licenses/by/4.0/
Except where otherwise noted, this item's licence is described as © 2023 Massachusetts Medical Society. This version is made available under the CC-BY 4.0 license: https://creativecommons.org/licenses/by/4.0/