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A copy number variation morbidity map of developmental delay

Nature Genetics volume 43, pages 838–846 (2011)Cite this article

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A Corrigendum to this article was published on 01 September 2014

A Corrigendum to this article was published on 01 September 2014

This article has been updated

Abstract

To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ∼14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.

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Figure 1: CNV size distributions in affected and unaffected individuals.
Figure 2: Maps of CNV locations for chromosomes 15 and 17.
Figure 3: Discovery of new microdeletions associated with genomic disorders.
Figure 4: Discovery of new, exon-altering CNVs using the Signature CGH data.

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Change history

  • 27 August 2014

    In the version of this article initially published, in Table 1 and its associated text, there was a calculation error in which the relative sizes of the case and control populations were set to be equal; because the size of the case population (15,767) was nearly double that of the control population (8,329), this resulted in erroneously inflated penetrance estimates. A simple definition of penetrance is used that is often applied in medical genetics—namely, the proportion of observed mutation carriers that are affected—to provide a metric that would be useful to clinical geneticists in a setting in which disease is heavily enriched, for example, in diagnosing children with developmental delay. That formulation is biased upwards with respect to population-level penetrance. Thus, in this corrigendum, an estimate more appropriate for population-level inference is provided assuming a general disease prevalence of 5.3% (Am. J. Hum. Genet. 42, 677–693, 1988) along with the more familiar odds ratio (OR) estimate. Importantly, all of these measures of penetrance are intrinsically limited by sampling error and imprecision in defining disease prevalence. We note that the mutation carrier counts, P values and other results in the original version of Table 1 are correct, and the key results and conclusions of the paper are unaffected. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Greenway, S.C. et al. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat. Genet. 41, 931–935 (2009).

    Article  CAS  Google Scholar 

  2. Mefford, H.C. et al. Recurrent reciprocal genomic rearrangements of 17q12 are associated with renal disease, diabetes, and epilepsy. Am. J. Hum. Genet. 81, 1057–1069 (2007).

    Article  CAS  Google Scholar 

  3. Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007).

    Article  CAS  Google Scholar 

  4. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).

    Article  CAS  Google Scholar 

  5. Walsh, T. et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543 (2008).

    Article  CAS  Google Scholar 

  6. Sharp, A.J. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat. Genet. 38, 1038–1042 (2006).

    Article  CAS  Google Scholar 

  7. Gu, W., Zhang, F. & Lupski, J.R. Mechanisms for human genomic rearrangements. Pathogenetics 1, 4 (2008).

    Article  Google Scholar 

  8. Girirajan, S. et al. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat. Genet. 42, 203–209 (2010).

    Article  CAS  Google Scholar 

  9. Mefford, H.C. et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N. Engl. J. Med. 359, 1685–1699 (2008).

    Article  CAS  Google Scholar 

  10. van Bon, B.W. et al. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J. Med. Genet. 46, 511–523 (2009).

    Article  CAS  Google Scholar 

  11. Shprintzen, R.J. Velocardiofacial syndrome and DiGeorge sequence. J. Med. Genet. 31, 423–424 (1994).

    Article  CAS  Google Scholar 

  12. Karayiorgou, M. et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc. Natl. Acad. Sci. USA 92, 7612–7616 (1995).

    Article  CAS  Google Scholar 

  13. Coe, B.P. et al. Resolving the resolution of array CGH. Genomics 89, 647–653 (2007).

    Article  CAS  Google Scholar 

  14. Cooper, G.M., Zerr, T., Kidd, J.M., Eichler, E.E. & Nickerson, D.A. Systematic assessment of copy number variant detection via genome-wide SNP genotyping. Nat. Genet. 40, 1199–1203 (2008).

    Article  CAS  Google Scholar 

  15. Itsara, A. et al. De novo rates and selection of large copy number variation. Genome Res. 20, 1469–1481 (2010).

    Article  CAS  Google Scholar 

  16. Itsara, A. et al. Population analysis of large copy number variants and hotspots of human genetic disease. Am. J. Hum. Genet. 84, 148–161 (2009).

    Article  CAS  Google Scholar 

  17. de Vries, B.B. et al. Diagnostic genome profiling in mental retardation. Am. J. Hum. Genet. 77, 606–616 (2005).

    Article  CAS  Google Scholar 

  18. Sharp, A.J., Cheng, Z. & Eichler, E.E. Structural variation of the human genome. Annu. Rev. Genomics Hum. Genet. 7, 407–442 (2006).

    Article  CAS  Google Scholar 

  19. Firth, H.V. et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am. J. Hum. Genet. 84, 524–533 (2009).

    Article  CAS  Google Scholar 

  20. Mefford, H.C. et al. A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Res. 19, 1579–1585 (2009).

    Article  CAS  Google Scholar 

  21. Walters, R.G. et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 463, 671–675 (2010).

    Article  CAS  Google Scholar 

  22. Bochukova, E.G. et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 463, 666–670 (2010).

    Article  CAS  Google Scholar 

  23. Helbig, I. et al. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat. Genet. 41, 160–162 (2009).

    Article  CAS  Google Scholar 

  24. Koolen, D.A. et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat. Genet. 38, 999–1001 (2006).

    Article  CAS  Google Scholar 

  25. Shaw-Smith, C. et al. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat. Genet. 38, 1032–1037 (2006).

    Article  CAS  Google Scholar 

  26. Zody, M.C. et al. Evolutionary toggling of the MAPT 17q21.31 inversion region. Nat. Genet. 40, 1076–1083 (2008).

    Article  CAS  Google Scholar 

  27. Suls, A. et al. Microdeletions involving the SCN1A gene may be common in SCN1A-mutation–negative SMEI patients. Hum. Mutat. 27, 914–920 (2006).

    Article  CAS  Google Scholar 

  28. Baroni, T. et al. Human cleft lip and palate fibroblasts and normal nicotine-treated fibroblasts show altered in vitro expressions of genes related to molecular signaling pathways and extracellular matrix metabolism. J. Cell. Physiol. 222, 748–756 (2010).

    CAS  PubMed  Google Scholar 

  29. Park, J.W. et al. High throughput SNP and expression analyses of candidate genes for non-syndromic oral clefts. J. Med. Genet. 43, 598–608 (2006).

    Article  CAS  Google Scholar 

  30. McCullumsmith, R.E. & Meador-Woodruff, J.H. Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder. Neuropsychopharmacology 26, 368–375 (2002).

    Article  CAS  Google Scholar 

  31. Chen, L., Chatterjee, M. & Li, J.Y. The mouse homeobox gene Gbx2 is required for the development of cholinergic interneurons in the striatum. J. Neurosci. 30, 14824–14834 (2010).

    Article  CAS  Google Scholar 

  32. Toh, K.L. et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291, 1040–1043 (2001).

    Article  CAS  Google Scholar 

  33. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  34. Brajenovic, M., Joberty, G., Kuster, B., Bouwmeester, T. & Drewes, G. Comprehensive proteomic analysis of human Par protein complexes reveals an interconnected protein network. J. Biol. Chem. 279, 12804–12811 (2004).

    Article  CAS  Google Scholar 

  35. Stalker, D.J., Vigneswaren, S., Sharples, P.M. & Lunt, P.W. Distal trisomy 2p and arachnodactyly. J. Med. Genet. 37, 974–976 (2000).

    Article  CAS  Google Scholar 

  36. Li, F., Batista, D.A., Maumenee, I. & Wang, T. An unbalanced translocation between chromosomes 2p and 6p associated with Axenfeld-Rieger anomaly type 3, hearing loss, developmental delay, and distinct facial dysmorphism. Am. J. Med. Genet. A. 152A, 1318–1321 (2010).

    Article  Google Scholar 

  37. Chaabouni, M. et al. De novo trisomy 20p of paternal origin. Am. J. Med. Genet. A. 143A, 1100–1103 (2007).

    Article  CAS  Google Scholar 

  38. Bowden, N.A., Scott, R.J. & Tooney, P.A. Altered gene expression in the superior temporal gyrus in schizophrenia. BMC Genomics 9, 199 (2008).

    Article  Google Scholar 

  39. Pruitt, K.D. et al. The consensus coding sequence (CCDS) project: identifying a common protein-coding gene set for the human and mouse genomes. Genome Res. 19, 1316–1323 (2009).

    Article  CAS  Google Scholar 

  40. Conrad, D.F., Andrews, T.D., Carter, N.P., Hurles, M.E. & Pritchard, J.K. A high-resolution survey of deletion polymorphism in the human genome. Nat. Genet. 38, 75–81 (2006).

    Article  CAS  Google Scholar 

  41. McCarroll, S.A. et al. Common deletion polymorphisms in the human genome. Nat. Genet. 38, 86–92 (2006).

    Article  CAS  Google Scholar 

  42. McCarroll, S.A. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat. Genet. 40, 1166–1174 (2008).

    Article  CAS  Google Scholar 

  43. Conrad, D.F. et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010).

    Article  CAS  Google Scholar 

  44. Kidd, J.M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64 (2008).

    Article  CAS  Google Scholar 

  45. Basson, C.T. et al. Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat. Genet. 15, 30–35 (1997).

    Article  CAS  Google Scholar 

  46. Brons, J.T. et al. Prenatal ultrasound diagnosis of the Holt-Oram syndrome. Prenat. Diagn. 8, 175–181 (1988).

    Article  CAS  Google Scholar 

  47. Turner, D.J. et al. Germline rates of de novo meiotic deletions and duplications causing several genomic disorders. Nat. Genet. 40, 90–95 (2008).

    Article  CAS  Google Scholar 

  48. Fisher, E. & Scambler, P. Human haploinsufficiency—one for sorrow, two for joy. Nat. Genet. 7, 5–7 (1994).

    Article  CAS  Google Scholar 

  49. Miller, D.T. et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am. J. Hum. Genet. 86, 749–764 (2010).

    Article  CAS  Google Scholar 

  50. Rudd, M.K. et al. Segmental duplications mediate novel, clinically relevant chromosome rearrangements. Hum. Mol. Genet. 18, 2957–2962 (2009).

    Article  CAS  Google Scholar 

  51. International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008).

  52. Boone, P.M. et al. Detection of clinically relevant exonic copy-number changes by array CGH. Hum. Mutat. 31, 1326–1342 (2010).

    Article  Google Scholar 

  53. Ropers, H.H. et al. Genetics of early onset cognitive impairment. Annu. Rev. Genomics Hum. Genet. 11, 161–187 (2010).

    Article  CAS  Google Scholar 

  54. Sayers, E.W. et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 39, D38–D51 (2011).

    Article  CAS  Google Scholar 

  55. Li, J.Z. et al. Worldwide human relationships inferred from genome-wide patterns of variation. Science 319, 1100–1104 (2008).

    Article  CAS  Google Scholar 

  56. Simon-Sanchez, J. et al. Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals. Hum. Mol. Genet. 16, 1–14 (2007).

    Article  CAS  Google Scholar 

  57. Albert, M.A., Danielson, E., Rifai, N. & Ridker, P.M. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. J. Am. Med. Assoc. 286, 64–70 (2001).

    Article  CAS  Google Scholar 

  58. Simon, J.A. et al. Phenotypic predictors of response to simvastatin therapy among African-Americans and Caucasians: the Cholesterol and Pharmacogenetics (CAP) Study. Am. J. Cardiol. 97, 843–850 (2006).

    Article  CAS  Google Scholar 

  59. Melzer, D. et al. A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet. 4, e1000072 (2008).

    Article  Google Scholar 

  60. Wellcome Trust Case Control Consortium. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464, 713–720 (2010).

  61. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank N. Krumm, M. Malig, L. Vives and J. Luu for assistance in validation experiments. We also thank M. Dennis, C. Alkan, E. Karakoc and T. Brown for useful discussions and for editing the manuscript. B.P.C. is supported by a fellowship from the Canadian Institutes of Health Research. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/. Funding for the project was provided by the Wellcome Trust under awards 076113 and 085475. We also thank A. Aragaki, C. Kooperberg and R. Jackson for access to SNP data (Fred Hutchinson Cancer Research Center (FHCRC) control dataset) generated as part of the ongoing genome-wide association study to identify genetic components of hip fracture in the Women's Health Initiative. This work was supported by US National Institutes of Health HD065285 to E.E.E. E.E.E. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

  1. Gregory M Cooper

    Present address: Present address: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.,

  2. Gregory M Cooper, Bradley P Coe and Santhosh Girirajan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genome Sciences, University of Washington, Seattle, Washington, USA

    Gregory M Cooper, Bradley P Coe, Santhosh Girirajan, Tiffany H Vu, Carl Baker & Evan E Eichler

  2. Signature Genomic Laboratories, LLC, Spokane, Washington, USA

    Jill A Rosenfeld, Blake C Ballif & Lisa G Shaffer

  3. Department of Pediatrics, Division of Genetics, University of Florida, Gainesville, Florida, USA

    Charles Williams & Heather Stalker

  4. Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Rizwan Hamid & Vickie Hannig

  5. Department of Pediatrics, Division of Child Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Hoda Abdel-Hamid

  6. Northeast Indiana Genetic Counseling Center, Ft. Wayne, Indiana, USA

    Patricia Bader

  7. Children's Hospital Pittsburgh, Pittsburgh, Pennsylvania, USA

    Elizabeth McCracken

  8. Ochsner Clinic, New Orleans, Louisiana, USA

    Dmitriy Niyazov

  9. Group Health Cooperative, Seattle, Washington, USA

    Kathleen Leppig & Heidi Thiese

  10. West Virginia University, Morgantown, West Virginia, USA

    Marybeth Hummel & Nora Alexander

  11. University of Missouri, Columbia, Missouri, USA

    Jerome Gorski & Jennifer Kussmann

  12. Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA

    Vandana Shashi

  13. Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA

    Krys Johnson

  14. Clinical Molecular Diagnostic Laboratory, Duke University Health System, Durham, North Carolina, USA

    Catherine Rehder

  15. Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA

    Evan E Eichler

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  1. Gregory M Cooper
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Contributions

G.M.C., B.P.C., S.G., E.E.E., J.A.R., B.C.B. and L.G.S. designed the study. L.G.S. supervised array-CGH experiments at Signature Genomics. J.A.R. and B.C.B. coordinated clinical data collection. G.M.C. and B.P.C. performed data analysis and curated control CNV data. S.G. curated genomic disorders data. S.G., T.H.V. and C.B. performed array CGH and PCR validations. C.W., H.S., R.H., V.H., H.A.-H., P.B., E.M., D.N., K.L., H.T., M.H., N.A., J.G., J.K., V.S., K.J. and C.R. provided clinical information. G.M.C., B.P.C., S.G. and E.E.E. wrote the manuscript. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Evan E Eichler.

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Competing interests

E.E.E. is a member of the Scientific Advisory Board of Pacific Biosciences. J.A.R., B.C.B. and L.G.S. are employees of PerkinElmer.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 2–11, Supplementary Figures 1–13 and Supplementary Note. (PDF 3185 kb)

Supplementary Table 1

Phenotype by sample (XLSX 683 kb)

Supplementary Table 12

Gene level statistics (XLSX 5069 kb)

Supplementary Table 13

Control CNV burden by gene (XLSX 2814 kb)

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Cooper, G., Coe, B., Girirajan, S. et al. A copy number variation morbidity map of developmental delay. Nat Genet 43, 838–846 (2011). https://doi.org/10.1038/ng.909

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