Dataset Information

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.

SUBMITTER: King DA

PROVIDER: S-EPMC4406290 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Mosaic structural variation in children with developmental disorders.

King Daniel A DA Jones Wendy D WD Crow Yanick J YJ Dominiczak Anna F AF Foster Nicola A NA Gaunt Tom R TR Harris Jade J Hellens Stephen W SW Homfray Tessa T Innes Josie J Jones Elizabeth A EA Joss Shelagh S Kulkarni Abhijit A Mansour Sahar S Morris Andrew D AD Parker Michael J MJ Porteous David J DJ Shihab Hashem A HA Smith Blair H BH Tatton-Brown Katrina K Tolmie John L JL Trzaskowski Maciej M Vasudevan Pradeep C PC Wakeling Emma E Wright Michael M Plomin Robert R Timpson Nicholas J NJ Hurles Matthew E ME

Human molecular genetics 20150129 10

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 mut ...[more]

PMID: 25634561

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Project description:BackgroundRisk of being diagnosed with different developmental disorders is found to vary with immigrant background. Knowledge about such differences in Norway are a starting point for equity in health services quality, and for early identification and prevention. Our objective was to assess the risk of receiving diagnoses of developmental disorders among children born in Norway (2006-2017) to two or one immigrant parent compared to children with two Norwegian-born parents.MethodsInformation on developmental disorders was from the Norwegian Patient Register (NPR) and information on immigrant background, parental country of origin, parental education, and household income from Statistics Norway. We estimated hazard ratios (HR) with Cox proportional hazard regressions. With children with Norwegian background as reference category, we estimated HRs for immigration background and region of origin. All analyses were adjusted for sex, year of birth, parental education, and household income.ResultsChildren with two immigrant parents had a lower risk of receiving any developmental disorder diagnosis [HR 0.80 (95% CI 0.77, 0.82)] than children with Norwegian background, and lower risk of being diagnosed with attention deficit hyperactivity disorder (ADHD) diagnosis [HR 0.24 (95% CI 0.22, 0.27)], learning difficulties diagnosis [HR 0.39 (95% CI 0.33, 0.47)], and behavioral and emotional disorders [HR 0.52 (95% CI 0.49, 0.55)]. Children with immigrant parents had higher hazard than Norwegian background children of autism spectrum disorder (ASD) [HR 2.21 (95% CI 2.04, 2.39)], mental retardation [HR 1.84 (95% CI 1.64, 2.07)], language disorders [HR 1.30 (95% CI 1.20, 1.40)], and unspecified developmental disorders [HR 1.22 (95% CI 1.17, 1.28)]. Children with only one immigrant parent had lower risk of diagnoses than children of two immigrants.ConclusionRisk of receiving a diagnosis of various developmental disorders varied substantially by immigrant background. Understanding the underlying mechanisms of these differences is warranted to ensure equity in health services and timely intervention.

Dataset Information

Mosaic structural variation in children with developmental disorders.

Publications

Mosaic structural variation in children with developmental disorders.

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