title: Mosaic structural variation in children with developmental disorders.
abstract: Delineating the genetic causes of developmental disorders is an area of active investigation. Mosaic structural abnormalities, defined as copy number or loss of heterozygosity events that are large and present in only a subset of cells, have been detected in 0.2-1.0% of children ascertained for clinical genetic testing. However, the frequency among healthy children in the community is not well characterized, which, if known, could inform better interpretation of the pathogenic burden of this mutational category in children with developmental disorders. In a case-control analysis, we compared the rate of large-scale mosaicism between 1303 children with developmental disorders and 5094 children lacking developmental disorders, using an analytical pipeline we developed, and identified a substantial enrichment in cases (odds ratio = 39.4, P-value 1.073e - 6). A meta-analysis that included frequency estimates among an additional 7000 children with congenital diseases yielded an even stronger statistical enrichment (P-value 1.784e - 11). In addition, to maximize the detection of low-clonality events in probands, we applied a trio-based mosaic detection algorithm, which detected two additional events in probands, including an individual with genome-wide suspected chimerism. In total, we detected 12 structural mosaic abnormalities among 1303 children (0.9%). Given the burden of mosaicism detected in cases, we suspected that many of the events detected in probands were pathogenic. Scrutiny of the genotypic-phenotypic relationship of each detected variant assessed that the majority of events are very likely pathogenic. This work quantifies the burden of structural mosaicism as a cause of developmental disorders.
authors: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors: Daniel A
authors: DA
authors: King
authors: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors: Wendy D
authors: WD
authors: Jones
authors: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, NHS Foundation Trust, Manchester Academic Health Science Centre (MAHSC), Manchester M13 9WL, UK.
authors: Yanick J
authors: YJ
authors: Crow
authors: College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors: Anna F
authors: AF
authors: Dominiczak
authors: University Hospitals of Leicester, NHS Trust, Leicester Royal Infirmary, Leicester LE1 5WW, UK.
authors: Nicola A
authors: NA
authors: Foster
authors: MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors: Tom R
authors: TR
authors: Gaunt
authors: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, NHS Foundation Trust, Manchester Academic Health Science Centre (MAHSC), Manchester M13 9WL, UK.
authors: Jade
authors: J
authors: Harris
authors: Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne NE1 3BZ, UK.
authors: Stephen W
authors: SW
authors: Hellens
authors: Southwest Thames Regional Genetics Centre, St George's Healthcare NHS Trust, London SW17 0RE, UK.
authors: Tessa
authors: T
authors: Homfray
authors: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, NHS Foundation Trust, Manchester Academic Health Science Centre (MAHSC), Manchester M13 9WL, UK.
authors: Josie
authors: J
authors: Innes
authors: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, NHS Foundation Trust, Manchester Academic Health Science Centre (MAHSC), Manchester M13 9WL, UK, Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, MAHSC, Manchester M13 9WL, UK.
authors: Elizabeth A
authors: EA
authors: Jones
authors: West of Scotland Clinical Genetics Service, Southern General Hospital, Glasgow DD1 9SY, UK.
authors: Shelagh
authors: S
authors: Joss
authors: Southwest Thames Regional Genetics Centre, St George's Healthcare NHS Trust, London SW17 0RE, UK.
authors: Abhijit
authors: A
authors: Kulkarni
authors: Southwest Thames Regional Genetics Centre, St George's Healthcare NHS Trust, London SW17 0RE, UK.
authors: Sahar
authors: S
authors: Mansour
authors: School of Molecular, Genetic and Population Health Sciences, University of Edinburgh Medical School, Teviot Place, Edinburgh EH8 9AG, UK.
authors: Andrew D
authors: AD
authors: Morris
authors: Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank, Sheffield, UK.
authors: Michael J
authors: MJ
authors: Parker
authors: Medical Genetics Section, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors: David J
authors: DJ
authors: Porteous
authors: MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors: Hashem A
authors: HA
authors: Shihab
authors: School of Medicine, Dundee University, Mackenzie Building, Kirsty Semple Way, Ninewells Hospital and Medical School, Dundee DD2 4RB, UK.
authors: Blair H
authors: BH
authors: Smith
authors: Southwest Thames Regional Genetics Centre, St George's Healthcare NHS Trust, London SW17 0RE, UK.
authors: Katrina
authors: K
authors: Tatton-Brown
authors: West of Scotland Clinical Genetics Service, Southern General Hospital, Glasgow DD1 9SY, UK.
authors: John L
authors: JL
authors: Tolmie
authors: King's College London, MRC Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London SE5 8AF, UK and.
authors: Maciej
authors: M
authors: Trzaskowski
authors: University Hospitals of Leicester, NHS Trust, Leicester Royal Infirmary, Leicester LE1 5WW, UK.
authors: Pradeep C
authors: PC
authors: Vasudevan
authors: North West Thames Regional Genetics Service, North West London Hospitals NHS Trust, Watford Rd, Harrow HA1 3UJ, UK.
authors: Emma
authors: E
authors: Wakeling
authors: Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne NE1 3BZ, UK.
authors: Michael
authors: M
authors: Wright
authors: King's College London, MRC Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London SE5 8AF, UK and.
authors: Robert
authors: R
authors: Plomin
authors: MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors: Nicholas J
authors: NJ
authors: Timpson
authors: Matthew E
authors: ME
authors: Hurles
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D056914:Genomic Structural Variation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D055815:Young Adult
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