دورية أكاديمية
Genomic diagnosis of rare pediatric disease in the United Kingdom and Ireland
| العنوان: | Genomic diagnosis of rare pediatric disease in the United Kingdom and Ireland |
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| المؤلفون: | Wright, CF, Campbell, P, Eberhardt, RY, Aitken, S, Perrett, D, Brent, S, Danacek, P, Gardner, EJ, Chundru, VK, Lindsay, SJ, Andrews, K, Hampstead, J, Kaplanis, J, Samocha, KE, Middleton, A, Foreman, J, Hobson, RJ, Parker, MJ, Martin, HC, FitzPatrick, DR, Hurles, ME, Firth, HV |
| بيانات النشر: | Massachusetts Medical Society |
| سنة النشر: | 2023 |
| المجموعة: | University of Exeter: Open Research Exeter (ORE) |
| مصطلحات موضوعية: | genomic medicine, rare disease |
| الوصف: | This is the author accepted manuscript. The final version is available from the Massachusetts Medical Society via the DOI in this record ; Background: 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. ; Health Innovation Challenge Fund ; Wellcome Sanger Institute ; Wellcome Trust |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0028-4793 1533-4406 |
| العلاقة: | orcid:0000-0003-2958-5076 (Wright, Caroline); Published online 12 April 2023; HICF-1009-003; WT098051; WT223718/Z/21/Z; http://hdl.handle.net/10871/132594Test; New England Journal of Medicine |
| DOI: | 10.1056/NEJMoa2209046 |
| الإتاحة: | https://doi.org/10.1056/NEJMoa2209046Test http://hdl.handle.net/10871/132594Test |
| حقوق: | © 2023 Massachusetts Medical Society. This version is made available under the CC-BY 4.0 license: https://creativecommons.org/licenses/by/4.0Test/ ; https://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.CFD20AE7 |
| قاعدة البيانات: | BASE |
| تدمد: | 00284793 15334406 |
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| DOI: | 10.1056/NEJMoa2209046 |