Intellectual Disability: Genetics

Samantha JL Knight, University of Oxford, Oxford, UK

Published online: December 2008

DOI: 10.1002/9780470015902.a0005515.pub2

The extent to which genetics plays a role in intelligence has long been a matter for debate. However, it is now well established that genetic effects can contribute to intellectual disability (ID), in particular, moderate to severe ID. The discovery of chromosomal rearrangements and the cloning of causal genes have both clinical and scientific value. Clinically, they help the families of those affected by providing molecular diagnoses, alleviating feelings of guilt and allowing more accurate genetic counselling. Scientifically, they provide important clues regarding the underlying biology of cognition.

Key concepts

  • Both intellectual ability and disability are strongly influenced by genetics.
  • ID is usually divided into syndromic and nonsyndromic categories.
  • Most recognized forms of ID are X-chromosome linked.
  • Single gene mutations can cause syndromic and nonsyndromic ID.
  • Causative gene products can be biochemically linked, signposting functionally important processes.
  • Genome imbalance (aneusomy and segmental aneusomy) is a significant cause of syndromic ID.
  • Array comparative genomic hybridization is a powerful new technique for identifying submicroscopic genome imbalances.
  • Genome architecture can predispose to recurrent genomic disorders.
  • Clinically, the provision of a molecular diagnosis is important to families with affected members.

Keywords: mental retardation; learning disability; intelligence quotient; aneusomy; copy number variant; genomic disorder

Figure 1. Two-group hypothesis of intellectual disability. The explanation for the excess of low intelligence quotient (IQ) is shown as an additional curve superimposed to the left of a normal distribution that has its mean at 100.
Figure 2. Processes implicated in intellectual disability. Part (b) adapted from image available at http://www.jenabioscience.com/cms/en/t/browse/576_transcription_factors.html and reproduced with permission of Jena Bioscience GmBH.
close
 References
    Alarcón M, Abrahams BS, Stone JL et al. (2008) Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. American Journal of Human Genetics 82: 150–159.
    Arking DE, Cutler DJ, Brune CW et al. (2008) A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. American Journal of Human Genetics 82: 160–164.
    Bakkaloglu B, O'Roak BJ, Louvi A et al. (2008) Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. American Journal of Human Genetics 82: 165–173.
    Ballif BC, Hornor SA, Jenkins E et al. (2007) Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2. Nature Genetics 39: 1071–1073.
    Butcher LM, Kennedy JKJ and Plomin R (2006) Generalist genes and cognitive neuroscience. Current Opinion in Neurobiology 16: 145–151.
    Christian SL, Brune CW, Sudi J et al. (2008) Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biological Psychiatry 15: 1111–1117.
    Girirajan S, Elsas LJ II, Devriendt K and Elsea SH (2005) RAI1 variations in Smith–Magenis syndrome patients without 17p11.2 deletions. Journal of Medical Genetics 42: 820–828.
    Glass I (1991) X-linked mental retardation. Journal of Medical Genetics 28: 361–371.
    other Hannes FD, Sharp AJ, Mefford HC et al. (2008) 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. Journal of Medical Genetics (in press).
    Jamain S, Quach H, Betancur C et al. Paris Autism Research International Sibpair Study (2005) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Molecular Psychiatry 10: 329–332.
    Kirchhoff M, Bisgaard AM, Duno M, Hansen FJ and Schwartz M (2007) A 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features. European Journal of Medical Genetics 50: 256–263.
    Kishino T, Lalande M and Wagstaff J (1997) UBE3A/E6-AP mutations cause Angelman syndrome. Nature Genetics 15: 70–73.
    Kleefstra T, Yntema HG, Oudakker AR et al. (2004) Zinc finger 81 (ZNF81) mutations associated with X-linked mental retardation. Journal of Medical Genetics 41: 394–399.
    book Knight SJL (2005) "Subtelomeric rearrangements in unexplained mental retardation". In: Fuchs J and Podda M (eds) Encyclopedia of Medical Genomics and Proteomics, pp. 1246–1252. New York, NY: Marcel Dekker.
    Knight SJL and Regan R (2006) Idiopathic learning disability and genome imbalance. Cytogenetic and Genome Research 115: 215–224.
    Koolen DA, Vissers LE, Pfundt R et al. (2006) A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nature Genetics 38: 999–1001.
    Kooy RF, Willemsen R and Oostra BA (2000) Fragile X syndrome at the turn of the century. Molecular Medicine Today 6: 193–198.
    Kumar RA, KaraMohamed S, Sudi J et al. (2008) Recurrent 16p11.2 microdeletions in autism. Human Molecular Genetics 17: 628–638.
    Kwon YT, Balogh SA, Davydov IV et al. (2000) Altered activity, social behavior, and spatial memory in mice lacking the NTAN1p amidase and the asparagine branch of the N-end rule pathway. Molecular and Cellular Biology 20: 4135–4148.
    Liao J, Aggarwal VS, Nowotschin S et al. (2008) Identification of downstream genetic pathways of Tbx1 in the second heart field. Developmental Biology 316: 524–537.
    Lower KM, Turner G, Kerr BA et al. (2002) Mutations in PHF6 are associated with Börjeson–Forssman–Lehmann syndrome. Nature Genetics 32: 661–665.
    Lubs H, Abidi FE, Echeverri R et al. (2006) Golabi-Ito-Hall syndrome results from a missense mutation in the WW domain of the PQBP1 gene. Journal of Medical Genetics 43: e30.
    Lugtenberg D, Yntema HG, Banning MJ et al. (2006) ZNF674: a new kruppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation. American Journal of Human Genetics 78: 265–278.
    Matsuura T, Sutcliffe JS, Fang P et al. (1997) De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nature Genetics 15: 74–77.
    Mefford HC, Sharp AJ, Baker C et al. (2008) Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. New England Journal of Medicine 359: 1728–1730
    Messina MF, Zirilli G, Civa R et al. (2007) Neurocognitive profile in Turner's syndrome is not affected by growth impairment. Journal of Pedatric Endocrinology and Metabolism 20: 677–684.
    Nan X, Hou J, Maclean A et al. (2007) Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation. Proceedings of the National Academy of Sciences of the USA 104: 2709–2714.
    Paylor R, Glaser B, Mupo A et al. (2006) Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome. Proceedings of the National Academy of Sciences of the USA 103: 7729–7734.
    Plomin R and deFries JC (1998) The genetics of cognitive abilities and disabilities. Scientific American 278: 62–69.
    Reeve SP, Lin X, Sahin BH et al. (2008) Mutational analysis establishes a critical role for the N terminus of fragile X mental retardation protein FMRP. Journal of Neuroscience 28: 3221–3226.
    Roohi J, Montagna C, Tegay DH et al. (2008) Disruption of Contactin 4 in 3 subjects with autism spectrum disorder. Journal of Medical Genetics [Epub ahead of print]
    Ropers HH and Hamel BC (2005) X-linked mental retardation. Nature Reviews Genetics 6: 46–57.
    Sharp AJ, Hansen S, Selzer RR et al. (2006) Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nature Genetics 38: 1038–1042.
    Sharp AJ, Mefford HC, Li K et al. (2008) A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nature Genetics 40: 322–328.
    Sharp AJ, Selzer RR, Veltman JA et al. (2007) Characterization of a recurrent 15q24 microdeletion syndrome. Human Molecular Genetics 16: 567–572.
    Shaw-Smith C, Pittman AM, Willatt L et al. (2006) Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nature Genetics 38: 1032–1037.
    Shoichet SA, Hoffmann K, Menzel C et al. (2003) Mutations in the ZNF41 gene are associated with cognitive deficits: identification of a new candidate for X-linked mental retardation. American Journal of Human Genetics 73: 1341–1354.
    Stoller JZ and Epstein JA (2005) Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation. Human Molecular Genetics 14: 885–892.
    Sykes NH and Lamb JA (2007) Autism: the quest for the genes. Expert Reviews in Molecular Medicine 9: 1–15.
    Tarpey P, Parnau J, Blow M et al. (2004) Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation. American Journal of Human Genetics 75: 318–324.
    Underhill C, Qutob MS, Yee SP and Torchia J (2000) A novel nuclear receptor corepressor complex, N-CoR, contains components of the mammalian SWI/SNF complex and the corepressor KAP-1. Journal of Biological Chemistry 275: 40463–40470.
    Webb T, Maina EN, Soni S et al. (2008) In search of the psychosis gene in people with Prader-Willi syndrome. American Journal of Human Genetics A 146: 843–853.
    Weiss LA, Shen Y, Korn JM et al. Autism Consortium (2008) Association between microdeletion and microduplication at 16p11.2 and autism. New England Journal of Medicine 358: 737–739.
    Yagi H, Furutani Y, Hamada H et al. (2003) Role of TBX1 in human del22q11.2 syndrome. Lancet 362: 1366–1373.
 Further Reading
    Antonarakis SE (1998) 10 years of genomics, chromosome 21, and Down syndrome. Genomics 51: 1–16.
    Budarf ML and Emanuel BS (1997) Progress in the autosomal segmental aneusomy syndromes (SASs): single or multi-locus disorders. Human Molecular Genetics 6: 1657–1665.
    Flint J and Wilkie AOM (1996) The genetics of mental retardation. British Medical Bulletin 52: 453–464.
    Luo L (2000) Rho GTPases in neuronal morphogenesis. Nature Reviews Neuroscience 1: 173–180.
    Mitchell EB, Leonhard K, Stupca PJ, jalal SM and Lindor NM (2008) Ready reference to common segmental aneusomies by syndromic names, major features and chromosomeal locations. Journal of the Association of Genetic Technologists 34: 5–7.
    Nicholls RD, Saitoh S and Horsthemke B (1998) Imprinting in Prader–Willi and Angelman syndromes. Trends in Genetics 14: 194–200.
    book Penrose LS (1963) The Biology of Mental Defect. London: Sidgwick & Jackson.
    Raymond FL and Tarpey P (2006) The genetics of mental retardation. Human Molecular Genetics 15: R110–R116.
    Scambler PJ (2000) The 22q11 deletion syndromes. Human Molecular Genetics 9: 2421–2426.
    Slavotinek AM (2008) Novel microdeletion syndromes detected by chromosome microarrays. Human Genetics [Epub ahead of print].
    Zinn AR and Ross JL (1998) Turner syndrome and haploinsufficiency. Current Opinion in Genetics and Development 8: 322–327.

Related Sub-Topics:

Neurobiology of Disease | Nervous System Development | Neural Networks and Behaviour | Development of Vertebrate Nervous System | Developmental Disorders | Molecular Genetics of Common and Complex Disease | Genetics of Intelligence and Cognition | Specific Genetic Disorders | Genomic Disorders
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Intellectual Disability: Genetics
 
How to Cite close
Knight, Samantha JL(Dec 2008) Intellectual Disability: Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005515.pub2]