• Caroline F Wright, Patrick Campbell, Ruth Y Eberhardt, Stuart Aitken, Daniel Perrett, Simon Brent, Petr Danecek, Eugene J Gardner, V Kartik Chundru, Sarah J Lindsay, Katrina Andrews, Juliet Hampstead, Joanna Kaplanis, Kaitlin E Samocha, Anna Middleton, Julia Foreman, Rachel J Hobson, Michael J Parker, Hilary C Martin, David R FitzPatrick, Matthew E Hurles, Helen V Firth, and DDD Study.
• From 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.
• N. Engl. J. Med. 2023 Apr 27; 388 (17): 155915711559-1571.

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.).Copyright © 2023 Massachusetts Medical Society.

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