Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Microduplication syndromes

Carlos A Bacino, MD, FACMG
Section Editor
Helen V Firth, DM, FRCP, DCH
Deputy Editor
Elizabeth TePas, MD, MS


Microduplications, or submicroscopic duplications, are chromosomal duplications that are too small to be detected by light microscopy using conventional cytogenetics methods. Specialized testing is needed to identify these duplications. Microduplications are typically one to three megabases (Mb) long and involve several contiguous genes. The exact size and location of a microduplication that causes a syndrome may vary, but a specific "critical region" may be consistently involved. Most of the phenotypic effects of these microduplications are due to changes in a few critical dose-sensitive genes or, in some cases, a single gene if a duplication disrupts its integrity.

The phenotype of microduplication syndromes is often less clear and less well defined than for the corresponding microdeletion syndrome. In addition, some microduplication syndromes may be inherited from apparently normal parents, raising important issues regarding incomplete penetrance and ascertainment bias in these newly described clinical entities.

This topic reviews microduplication syndromes of chromosomes 1 to 22. Microdeletion syndromes, congenital abnormalities of the sex chromosomes, and other congenital chromosomal abnormalities, such as trisomies, are reviewed in detail elsewhere. (See "Microdeletion syndromes (chromosomes 1 to 11)" and "Microdeletion syndromes (chromosomes 12 to 22)" and "Sex chromosome abnormalities" and "Congenital cytogenetic abnormalities".)


Genomic disorders are diseases that result from the loss or gain of chromosomal/DNA material. The most common and better delineated genomic disorders are divided in two main categories: those resulting from copy number losses (deletion syndromes) and those resulting from copy number gains (duplication syndromes). (See "Genomic disorders: An overview".)

Copy number variations (CNVs) are submicroscopic genomic differences in the number of copies of one or more sections of DNA that result in DNA gains or losses (figure 1). Some CNVs are pathogenic and cause syndromic disorders with consistent phenotypic features, as are discussed here. Other CNVs are associated with disease susceptibility or resistance, and the same CNV can be associated with several diverse disorders. Still, other CNVs are part of normal genetic variation and have no recognized disease association. Contiguous gene syndromes can occur when CNVs affect several adjacent genes. (See "Overview of genetic variation", section on 'Copy number variations (CNVs)' and "Basic principles of genetic disease", section on 'Copy number variation'.)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Oct 2017. | This topic last updated: Jun 24, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. 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.
  2. 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.
  3. Dolcetti A, Silversides CK, Marshall CR, et al. 1q21.1 Microduplication expression in adults. Genet Med 2013; 15:282.
  4. Digilio MC, Bernardini L, Consoli F, et al. Congenital heart defects in recurrent reciprocal 1q21.1 deletion and duplication syndromes: rare association with pulmonary valve stenosis. Eur J Med Genet 2013; 56:144.
  5. Kantaputra PN, Klopocki E, Hennig BP, et al. Mesomelic dysplasia Kantaputra type is associated with duplications of the HOXD locus on chromosome 2q. Eur J Hum Genet 2010; 18:1310.
  6. Cho TJ, Kim OH, Choi IH, et al. A dominant mesomelic dysplasia associated with a 1.0-Mb microduplication of HOXD gene cluster at 2q31.1. J Med Genet 2010; 47:638.
  7. Cukier HN, Lee JM, Ma D, et al. The expanding role of MBD genes in autism: identification of a MECP2 duplication and novel alterations in MBD5, MBD6, and SETDB1. Autism Res 2012; 5:385.
  8. Mullegama SV, Rosenfeld JA, Orellana C, et al. Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder. Eur J Hum Genet 2014; 22:57.
  9. 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.
  10. Goobie S, Knijnenburg J, Fitzpatrick D, et al. Molecular and clinical characterization of de novo and familial cases with microduplication 3q29: guidelines for copy number variation case reporting. Cytogenet Genome Res 2008; 123:65.
  11. Lisi EC, Hamosh A, Doheny KF, et al. 3q29 interstitial microduplication: a new syndrome in a three-generation family. Am J Med Genet A 2008; 146A:601.
  12. Franco LM, de Ravel T, Graham BH, et al. A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion. Eur J Hum Genet 2010; 18:258.
  13. Zhang H, Lu X, Beasley J, et al. Reversed clinical phenotype due to a microduplication of Sotos syndrome region detected by array CGH: microcephaly, developmental delay and delayed bone age. Am J Med Genet A 2011; 155A:1374.
  14. Sanders SJ, Ercan-Sencicek AG, Hus V, et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 2011; 70:863.
  15. Berg JS, Brunetti-Pierri N, Peters SU, et al. Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region. Genet Med 2007; 9:427.
  16. Torniero C, Dalla Bernardina B, Novara F, et al. Dysmorphic features, simplified gyral pattern and 7q11.23 duplication reciprocal to the Williams-Beuren deletion. Eur J Hum Genet 2008; 16:880.
  17. Morris CA, Mervis CB, Paciorkowski AP, et al. 7q11.23 Duplication syndrome: Physical characteristics and natural history. Am J Med Genet A 2015; 167A:2916.
  18. Zarate YA, Lepard T, Sellars E, et al. Cardiovascular and genitourinary anomalies in patients with duplications within the Williams syndrome critical region: phenotypic expansion and review of the literature. Am J Med Genet A 2014; 164A:1998.
  19. Baker P, Piven J, Schwartz S, Patil S. Brief report: duplication of chromosome 15q11-13 in two individuals with autistic disorder. J Autism Dev Disord 1994; 24:529.
  20. Bolton PF, Dennis NR, Browne CE, et al. The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders. Am J Med Genet 2001; 105:675.
  21. Piard J, Philippe C, Marvier M, et al. Clinical and molecular characterization of a large family with an interstitial 15q11q13 duplication. Am J Med Genet A 2010; 152A:1933.
  22. Bundey S, Hardy C, Vickers S, et al. Duplication of the 15q11-13 region in a patient with autism, epilepsy and ataxia. Dev Med Child Neurol 1994; 36:736.
  23. Flejter WL, Bennett-Baker PE, Ghaziuddin M, et al. Cytogenetic and molecular analysis of inv dup(15) chromosomes observed in two patients with autistic disorder and mental retardation. Am J Med Genet 1996; 61:182.
  24. 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.
  25. Williams NM, Franke B, Mick E, et al. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am J Psychiatry 2012; 169:195.
  26. Zhou D, Gochman P, Broadnax DD, et al. 15q13.3 duplication in two patients with childhood-onset schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2016; 171:777.
  27. Stewart LR, Hall AL, Kang SH, et al. High frequency of known copy number abnormalities and maternal duplication 15q11-q13 in patients with combined schizophrenia and epilepsy. BMC Med Genet 2011; 12:154.
  28. El-Hattab AW, Smolarek TA, Walker ME, et al. Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping. Hum Genet 2009; 126:589.
  29. Kiholm Lund AB, Hove HD, Kirchhoff M. A 15q24 microduplication, reciprocal to the recently described 15q24 microdeletion, in a boy sharing clinical features with 15q24 microdeletion syndrome patients. Eur J Med Genet 2008; 51:520.
  30. Marangi G, Leuzzi V, Orteschi D, et al. Duplication of the Rubinstein-Taybi region on 16p13.3 is associated with a distinctive phenotype. Am J Med Genet A 2008; 146A:2313.
  31. Thienpont B, Béna F, Breckpot J, et al. Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome. J Med Genet 2010; 47:155.
  32. Nagamani SC, Erez A, Bader P, et al. Phenotypic manifestations of copy number variation in chromosome 16p13.11. Eur J Hum Genet 2011; 19:280.
  33. Ramalingam A, Zhou XG, Fiedler SD, et al. 16p13.11 duplication is a risk factor for a wide spectrum of neuropsychiatric disorders. J Hum Genet 2011; 56:541.
  34. 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.
  35. 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.
  36. Kumar RA, Marshall CR, Badner JA, et al. Association and mutation analyses of 16p11.2 autism candidate genes. PLoS One 2009; 4:e4582.
  37. Kumar RA, KaraMohamed S, Sudi J, et al. Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet 2008; 17:628.
  38. McCarthy SE, Makarov V, Kirov G, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 2009; 41:1223.
  39. Michaud JL, Lachance M, Hamdan FF, et al. The genetic landscape of infantile spasms. Hum Mol Genet 2014; 23:4846.
  40. Reinthaler EM, Lal D, Lebon S, et al. 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy. Hum Mol Genet 2014; 23:6069.
  41. Schaaf CP, Goin-Kochel RP, Nowell KP, et al. Expanding the clinical spectrum of the 16p11.2 chromosomal rearrangements: three patients with syringomyelia. Eur J Hum Genet 2011; 19:152.
  42. Hippolyte L, Maillard AM, Rodriguez-Herreros B, et al. The Number of Genomic Copies at the 16p11.2 Locus Modulates Language, Verbal Memory, and Inhibition. Biol Psychiatry 2016; 80:129.
  43. D'Angelo D, Lebon S, Chen Q, et al. Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities. JAMA Psychiatry 2016; 73:20.
  44. Bruno DL, Anderlid BM, Lindstrand A, et al. Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes. J Med Genet 2010; 47:299.
  45. Bi W, Sapir T, Shchelochkov OA, et al. Increased LIS1 expression affects human and mouse brain development. Nat Genet 2009; 41:168.
  46. Potocki L, Bi W, Treadwell-Deering D, et al. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet 2007; 80:633.
  47. Potocki L, Chen KS, Park SS, et al. Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat Genet 2000; 24:84.
  48. Yusupov R, Roberts AE, Lacro RV, et al. Potocki-Lupski syndrome: an inherited dup(17)(p11.2p11.2) with hypoplastic left heart. Am J Med Genet A 2011; 155A:367.
  49. Carmona-Mora P, Walz K. Retinoic Acid Induced 1, RAI1: A Dosage Sensitive Gene Related to Neurobehavioral Alterations Including Autistic Behavior. Curr Genomics 2010; 11:607.
  50. Soler-Alfonso C, Motil KJ, Turk CL, et al. Potocki-Lupski syndrome: a microduplication syndrome associated with oropharyngeal dysphagia and failure to thrive. J Pediatr 2011; 158:655.
  51. Sanchez-Valle A, Pierpont ME, Potocki L. The severe end of the spectrum: Hypoplastic left heart in Potocki-Lupski syndrome. Am J Med Genet A 2011; 155A:363.
  52. Kirchhoff M, Bisgaard AM, Duno M, et al. A 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features. Eur J Med Genet 2007; 50:256.
  53. Grisart B, Willatt L, Destrée A, et al. 17q21.31 microduplication patients are characterised by behavioural problems and poor social interaction. J Med Genet 2009; 46:524.
  54. Ensenauer RE, Adeyinka A, Flynn HC, et al. Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients. Am J Hum Genet 2003; 73:1027.
  55. Ou Z, Berg JS, Yonath H, et al. Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes. Genet Med 2008; 10:267.
  56. Yobb TM, Somerville MJ, Willatt L, et al. Microduplication and triplication of 22q11.2: a highly variable syndrome. Am J Hum Genet 2005; 76:865.
  57. Rees E, Kirov G, Sanders A, et al. Evidence that duplications of 22q11.2 protect against schizophrenia. Mol Psychiatry 2014; 19:37.
  58. Courtens W, Schramme I, Laridon A. Microduplication 22q11.2: a benign polymorphism or a syndrome with a very large clinical variability and reduced penetrance?--Report of two families. Am J Med Genet A 2008; 146A:758.
  59. Wentzel C, Fernström M, Ohrner Y, et al. Clinical variability of the 22q11.2 duplication syndrome. Eur J Med Genet 2008; 51:501.
  60. Okamoto N, Kubota T, Nakamura Y, et al. 22q13 Microduplication in two patients with common clinical manifestations: a recognizable syndrome? Am J Med Genet A 2007; 143A:2804.
  61. Frye RE. Mitochondrial disease in 22q13 duplication syndrome. J Child Neurol 2012; 27:942.