Skip to main content

Advertisement

Log in

Copy Number Variants: A New Molecular Frontier in Clinical Psychiatry

  • Published:
Current Psychiatry Reports Aims and scope Submit manuscript

Abstract

Molecular genetic research, building on genetic epidemiology, has provided the field of psychiatry with a host of exciting advances. It is now clear beyond any reasonable doubt that genetic inheritance influences liability to develop almost every major psychiatric disorder. Rapid progress in identifying genes contributing to psychiatric liability, recently accelerated by the advent of approaches such as genome-wide association studies and chromosomal microarray analysis, raises a critical question for psychiatric practice and training: how will molecular genetics alter the practice of psychiatry for front-line clinicians? The premise of the present review is that our growing knowledge regarding the roles of copy number variants in behavioral disorders will soon require revision of standards of evaluation and care for psychiatric patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of major importance

  1. Zhang F, Gu W, Hurles ME, Lupski JR. Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet. 2009;10:451–81.

    Article  PubMed  CAS  Google Scholar 

  2. Bassett AS, Chow EW. 22q11 deletion syndrome: a genetic subtype of schizophrenia. Biol Psychiatry. 1999;46:882–91.

    Article  PubMed  CAS  Google Scholar 

  3. • Miller DT, Aradhya S, Biesecker LG, et al.: Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. American Journal of Human Genetics 2010; 86: 749–764. In this recent review, the authors establish the importance and yield of CMA in patients with developmental disabilities and suggest using this resource as a first-tier diagnostic tool.

  4. Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455:232–6.

    Article  PubMed  CAS  Google Scholar 

  5. Consortium IS. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008;455:237–41.

    Article  Google Scholar 

  6. McCarthy SE, Makarov V, Kirov G, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009;41:1223–7.

    Article  PubMed  CAS  Google Scholar 

  7. Need AC, Ge D, Weale ME, et al. A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genet. 2009;5:e1000373.

    Article  PubMed  Google Scholar 

  8. Kirov G, Grozeva D, Norton N, et al. Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Hum Mol Genet. 2009;18:1497–503.

    Article  PubMed  CAS  Google Scholar 

  9. Nagamani SC, Erez A, Shen J, et al. Clinical spectrum associated with recurrent genomic rearrangements in chromosome 17q12. Eur J Hum Genet. 2010;18:278–84.

    Article  PubMed  CAS  Google Scholar 

  10. Loirat C, Bellanne-Chantelot C, Husson I, Deschenes G, Guigonis V, Chabane N. Autism in three patients with cystic or hyperechogenic kidneys and chromosome 17q12 deletion. Nephrol Dial Transplant. 2010;25:3430–3.

    Article  PubMed  CAS  Google Scholar 

  11. Ben-Shachar S, Lanpher B, German JR, et al. Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J Med Genet. 2009;46:382–8.

    Article  PubMed  CAS  Google Scholar 

  12. Tam GW, Redon R, Carter NP, Grant SG. The role of DNA copy number variation in schizophrenia. Biol Psychiatry. 2009;66:1005–12.

    Article  PubMed  CAS  Google Scholar 

  13. • Bassett AS, Scherer SW, Brzustowicz LM: Copy number variations in schizophrenia: critical review and new perspectives on concepts of genetics and disease. Am J Psychiatry 2010, 167:899–914. This review assesses comprehensively the most recent evidence for the role of DNA copy number variation in schizophrenia, as well as the mechanism through which it arises and the clinical repercussions. It also portrays the genetic and etiologic heterogeneity of schizophrenia and other related neurodevelopmental disorders.

  14. Taiminen T, Ranta K, Karlsson H, et al. Comparison of clinical and best-estimate research DSM-IV diagnoses in a Finnish sample of first-admission psychosis and severe affective disorder. Nord J Psychiatry. 2001;55:107–11.

    Article  PubMed  CAS  Google Scholar 

  15. Fennig S, Craig TJ, Tanenberg-Karant M, Bromet EJ. Comparison of facility and research diagnoses in first-admission psychotic patients. Am J Psychiatry. 1994;151:1423–9.

    PubMed  CAS  Google Scholar 

  16. Moilanen K, Veijola J, Laksy K, et al. Reasons for the diagnostic discordance between clinicians and researchers in schizophrenia in the Northern Finland 1966 Birth Cohort. Soc Psychiatry Psychiatr Epidemiol. 2003;38:305–10.

    PubMed  Google Scholar 

  17. Kirkby KC, Hay DA, Daniels BA, Jones IH, Mowry BJ. Comparison between register and structured interview diagnoses of schizophrenia: a case for longitudinal diagnostic profiles. Aust N Z J Psychiatry. 1998;32:410–4.

    Article  PubMed  CAS  Google Scholar 

  18. Makikyro T, Isohanni M, Moring J, Hakko H, Hovatta I, Lonnqvist J. Accuracy of register-based schizophrenia diagnoses in a genetic study. Eur Psychiatry. 1998;13:57–62.

    Article  PubMed  CAS  Google Scholar 

  19. Bassett AS, Costain G, Alan Fung WL et al: Clinically detectable copy number variations in a Canadian catchment population of schizophrenia. J Psychiatr Res 2010.

  20. Ousley O, Rockers K, Dell ML, Coleman K, Cubells JF. A review of neurocognitive and behavioral profiles associated with 22q11 deletion syndrome: implications for clinical evaluation and treatment. Curr Psychiatry Rep. 2007;9:148–58.

    Article  PubMed  Google Scholar 

  21. Golding-Kushner KJ, Weller G, Shprintzen RJ. Velo-cardio-facial syndrome: language and psychological profiles. J Craniofac Genet Dev Biol. 1985;5:259–66.

    PubMed  CAS  Google Scholar 

  22. Shprintzen RJ, Goldberg R, Golding-Kushner KJ, Marion RW. Late-onset psychosis in the velo-cardio-facial syndrome. Am J Med Genet. 1992;42:141–2.

    Article  PubMed  CAS  Google Scholar 

  23. Pulver AE, Nestadt G, Goldberg R, et al. Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J Nerv Ment Dis. 1994;182:476–8.

    Article  PubMed  CAS  Google Scholar 

  24. Karayiorgou M, Morris MA, Morrow B, et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci U S A. 1995;92:7612–6.

    Article  PubMed  CAS  Google Scholar 

  25. Hoogendoorn ML, Vorstman JA, Jalali GR, et al. Prevalence of 22q11.2 deletions in 311 Dutch patients with schizophrenia. Schizophr Res. 2008;98:84–8.

    Article  PubMed  Google Scholar 

  26. Vorstman JA, Morcus ME, Duijff SN, et al. The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. J Am Acad Child Adolesc Psychiatry. 2006;45:1104–13.

    Article  PubMed  Google Scholar 

  27. Bruining H, de Sonneville L, Swaab H, et al. Dissecting the clinical heterogeneity of autism spectrum disorders through defined genotypes. PLoS One. 2010;5:e10887.

    Article  PubMed  Google Scholar 

  28. Kane JM, Honigfeld G, Singer J, Meltzer H. Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull. 1988;24:62–7.

    PubMed  CAS  Google Scholar 

  29. Caluseriu O, Tayyeb T, Chow E, Bassett AS. Clozapine-associated seizures in a 22q deletion syndrome subtype of schizophrenia. Schizophr Res. 2007;60:70.

    Google Scholar 

  30. Mefford HC, Sharp AJ, Baker C, et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008;359:1685–99.

    Article  PubMed  CAS  Google Scholar 

  31. Brunetti-Pierri N, Berg JS, Scaglia F, et al. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet. 2008;40:1466–71.

    Article  PubMed  CAS  Google Scholar 

  32. Girirajan S, Eichler EE. Phenotypic variability and genetic susceptibility to genomic disorders. Hum Mol Genet. 2010;19:R176–187.

    Article  PubMed  CAS  Google Scholar 

  33. Ni X, Valente J, Azevedo MH, Pato MT, Pato CN, Kennedy JL. Connexin 50 gene on human chromosome 1q21 is associated with schizophrenia in matched case control and family-based studies. J Med Genet. 2007;44:532–6.

    Article  PubMed  CAS  Google Scholar 

  34. Willatt L, Cox J, Barber J, et al. 3q29 microdeletion syndrome: clinical and molecular characterization of a new syndrome. Am J Hum Genet. 2005;77:154–60.

    Article  PubMed  CAS  Google Scholar 

  35. Cotter L, Ozcelik M, Jacob C, et al. Dlg1-PTEN interaction regulates myelin thickness to prevent damaging peripheral nerve overmyelination. Science. 2010;328:1415–8.

    Article  PubMed  CAS  Google Scholar 

  36. Howard MA, Elias GM, Elias LA, Swat W, Nicoll RA. The role of SAP97 in synaptic glutamate receptor dynamics. Proc Natl Acad Sci U S A. 2010;107:3805–10.

    Article  PubMed  CAS  Google Scholar 

  37. Gaspar PA, Bustamante ML, Silva H, Aboitiz F. Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: therapeutic implications. J Neurochem. 2009;111:891–900.

    Article  PubMed  CAS  Google Scholar 

  38. Kreis P, Barnier JV. PAK signalling in neuronal physiology. Cell Signal. 2009;21:384–93.

    Article  PubMed  CAS  Google Scholar 

  39. Mignon-Ravix C, Depetris D, Luciani JJ, et al. Recurrent rearrangements in the proximal 15q11-q14 region: a new breakpoint cluster specific to unbalanced translocations. Eur J Hum Genet. 2007;15:432–40.

    Article  PubMed  CAS  Google Scholar 

  40. Miller DT, Shen Y, Weiss LA, et al. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet. 2009;46:242–8.

    Article  PubMed  CAS  Google Scholar 

  41. Pagnamenta AT, Wing K, Akha ES, et al. A 15q13.3 microdeletion segregating with autism. Eur J Hum Genet. 2009;17:687–92.

    Article  PubMed  CAS  Google Scholar 

  42. Sharp AJ, Mefford HC, Li K, et al. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet. 2008;40:322–8.

    Article  PubMed  CAS  Google Scholar 

  43. Dibbens LM, Mullen S, Helbig I, et al. Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Hum Mol Genet. 2009;18:3626–31.

    Article  PubMed  CAS  Google Scholar 

  44. Freedman R, Coon H, Myles-Worsley M, et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci U S A. 1997;94:587–92.

    Article  PubMed  CAS  Google Scholar 

  45. Leonard S, Gault J, Moore T, et al. Further investigation of a chromosome 15 locus in schizophrenia: analysis of affected sibpairs from the NIMH Genetics Initiative. Am J Med Genet. 1998;81:308–12.

    Article  PubMed  CAS  Google Scholar 

  46. Cubells J, DeOreo E, Harvey P et al: Pharmaco-genetically guided treatment of recurrent rage outbursts in an adult male with 15q13.3 deletion syndrome American J Med Genet, Part A 2011; in press.

  47. Weiss LA, Shen Y, Korn JM, et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. 2008;358:667–75.

    Article  PubMed  CAS  Google Scholar 

  48. Marshall CR, Noor A, Vincent JB, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82:477–88.

    Article  PubMed  CAS  Google Scholar 

  49. Kumar RA, KaraMohamed S, Sudi J, et al. Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet. 2008;17:628–38.

    Article  PubMed  CAS  Google Scholar 

  50. Fernandez BA, Roberts W, Chung B, et al. Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder. J Med Genet. 2010;47:195–203.

    Article  PubMed  Google Scholar 

  51. Shinawi M, Liu P, Kang SH, et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet. 2010;47:332–41.

    Article  PubMed  CAS  Google Scholar 

  52. Martin J, Han C, Gordon LA, et al. The sequence and analysis of duplication-rich human chromosome 16. Nature. 2004;432:988–94.

    Article  PubMed  CAS  Google Scholar 

  53. Ullmann R, Turner G, Kirchhoff M, et al. Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation. Hum Mutat. 2007;28:674–82.

    Article  PubMed  CAS  Google Scholar 

  54. Pinto D, Pagnamenta AT, Klei L, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466:368–72.

    Article  PubMed  CAS  Google Scholar 

  55. • Moreno-De-Luca D, Mulle JG, Kaminsky EB et al: Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. Am J Hum Genet 2010; 87: 618–630. This article establishes the relevance of recurrent CNVs—particularly deletions in 17q12—in the etiology of schizophrenia and ASDs, two different but related neurodevelopmental conditions. These data add to the growing body of evidence showing that in specific cases, schizophrenia and ASDs share a common genetic etiology.

  56. McCauley JL, Li C, Jiang L, et al. Genome-wide and Ordered-Subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates. BMC Med Genet. 2005;6:1.

    Article  PubMed  Google Scholar 

  57. A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 2001; 69: 570–581.

  58. Yonan AL, Alarcon M, Cheng R, et al. A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet. 2003;73:886–97.

    Article  PubMed  CAS  Google Scholar 

  59. Stone JL, Merriman B, Cantor RM, et al. Evidence for sex-specific risk alleles in autism spectrum disorder. Am J Hum Genet. 2004;75:1117–23.

    Article  PubMed  CAS  Google Scholar 

  60. Stone JL, Merriman B, Cantor RM, Geschwind DH, Nelson SF. High density SNP association study of a major autism linkage region on chromosome 17. Hum Mol Genet. 2007;16:704–15.

    Article  PubMed  CAS  Google Scholar 

  61. Bellanne-Chantelot C, Chauveau D, Gautier JF, et al. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med. 2004;140:510–7.

    PubMed  CAS  Google Scholar 

  62. Avraham O, Hadas Y, Vald L, et al. Transcriptional control of axonal guidance and sorting in dorsal interneurons by the Lim-HD proteins Lhx9 and Lhx1. Neural Dev. 2009;4:21.

    Article  PubMed  Google Scholar 

  63. Shawlot W, Behringer RR. Requirement for Lim1 in head-organizer function. Nature. 1995;374:425–30.

    Article  PubMed  CAS  Google Scholar 

  64. Bassett AS, Chow EW, Husted J, et al. Clinical features of 78 adults with 22q11 deletion syndrome. Am J Med Genet A. 2005;138:307–13.

    PubMed  Google Scholar 

  65. Botto LD, May K, Fernhoff PM, et al. A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics. 2003;112:101–7.

    Article  PubMed  Google Scholar 

  66. Rockers K, Ousley O, Sutton T, et al. Performance on the Modified Card Sorting Test and its relation to psychopathology in adolescents and young adults with 22q11.2 deletion syndrome. J Intellect Disabil Res. 2009;53:665–76.

    Article  PubMed  CAS  Google Scholar 

  67. Heinzen EL, Radtke RA, Urban TJ, et al. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet. 2010;86:707–18.

    Article  PubMed  CAS  Google Scholar 

  68. Hannes FD, Sharp AJ, Mefford HC, et al. Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J Med Genet. 2009;46:223–32.

    Article  PubMed  CAS  Google Scholar 

  69. Bachmann-Gagescu R, Mefford HC, Cowan C, et al. Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet Med. 2010;12:641–7.

    Article  PubMed  Google Scholar 

  70. Sampson MG, Coughlin CR, Kaplan P, et al. Evidence for a recurrent microdeletion at chromosome 16p11.2 associated with congenital anomalies of the kidney and urinary tract (CAKUT) and Hirschsprung disease. Am J Med Genet A. 2010;152A:2618–22.

    Article  PubMed  CAS  Google Scholar 

  71. Middeldorp A, Jagmohan-Changur S, van Eijk R, et al. Enrichment of low penetrance susceptibility loci in a Dutch familial colorectal cancer cohort. Cancer Epidemiol Biomarkers Prev. 2009;18:3062–7.

    Article  PubMed  CAS  Google Scholar 

  72. van Bon BW, Mefford HC, Menten B, 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. 2009;46:511–23.

    Article  PubMed  Google Scholar 

  73. Mulle JG, Dodd AF, McGrath JA, et al. Microdeletions of 3q29 confer high risk for schizophrenia. Am J Hum Genet. 2010;87:229–36.

    Article  PubMed  CAS  Google Scholar 

  74. Ballif BC, Theisen A, Coppinger J, et al. Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication. Mol Cytogenet. 2008;1:8.

    Article  PubMed  Google Scholar 

  75. Velinov M, Dolzhanskaya N. Clavicular pseudoarthrosis, anomalous coronary artery and extra crease of the fifth finger-previously unreported features in individuals with class II 1q21.1 microdeletions. Eur J Med Genet. 2010;53:213–6.

    Article  PubMed  Google Scholar 

  76. Abdolmaleky HM, Cheng KH, Faraone SV, et al. Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet. 2006;15:3132–45.

    Article  PubMed  CAS  Google Scholar 

  77. Bassett AS, Caluseriu O, Weksberg R, Young DA, Chow EW. Catechol-O-methyl transferase and expression of schizophrenia in 73 adults with 22q11 deletion syndrome. Biol Psychiatry. 2007;61:1135–40.

    Article  PubMed  CAS  Google Scholar 

  78. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics. 1996;6:243–50.

    Article  PubMed  CAS  Google Scholar 

  79. Munafo MR, Bowes L, Clark TG, Flint J. Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol Psychiatry. 2005;10:765–70.

    Article  PubMed  CAS  Google Scholar 

  80. Shifman S, Bronstein M, Sternfeld M, et al. A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet. 2002;71:1296–302.

    Article  PubMed  CAS  Google Scholar 

  81. Gogos JA, Santha M, Takacs Z, et al. The gene encoding proline dehydrogenase modulates sensorimotor gating in mice. Nat Genet. 1999;21:434–9.

    Article  PubMed  CAS  Google Scholar 

  82. Jacquet H, Raux G, Thibaut F, et al. PRODH mutations and hyperprolinemia in a subset of schizophrenic patients. Hum Mol Genet. 2002;11:2243–9.

    Article  PubMed  CAS  Google Scholar 

  83. Meechan DW, Tucker ES, Maynard TM, LaMantia AS. Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome. Proc Natl Acad Sci U S A. 2009;106:16434–45.

    Article  PubMed  CAS  Google Scholar 

  84. Shin HD, Park BL, Bae JS, et al. Association of ZDHHC8 polymorphisms with smooth pursuit eye movement abnormality. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:1167–72.

    PubMed  CAS  Google Scholar 

  85. Cheong HS, Park BL, Kim EM, et al. Association of RANBP1 haplotype with smooth pursuit eye movement abnormality. Am J Med Genet B Neuropsychiatr Genet. 2011;156:67–71.

    Article  PubMed  Google Scholar 

  86. Sinibaldi L, De Luca A, Bellacchio E, et al. Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia. Hum Mutat. 2004;24:534–5.

    Article  PubMed  Google Scholar 

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joseph F. Cubells.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moreno-De-Luca, D., Cubells, J.F. Copy Number Variants: A New Molecular Frontier in Clinical Psychiatry. Curr Psychiatry Rep 13, 129–137 (2011). https://doi.org/10.1007/s11920-011-0183-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11920-011-0183-5

Keywords

Navigation