X‐Linked Intellectual Disability Genetics


Intellectual disability (ID) is a common disability affecting 2–3% of the general population. X‐linked intellectual disability (XLID) disorders, caused by the defects of genes on the X chromosome, affect 1.7 of 1000 males. Patients with XLID require long‐term family involvement, medical care and social services with enormous attendant burden and cost.

XLID is a medically important and biologically significant group of disorders for which the prospects for further progress on the understanding of their molecular basis have improved with advances in technological approaches. As such, worldwide efforts over the past 25 years have identified 124 XLID genes involved in 124 XLID syndromes and 53 nonsyndromal XLID conditions. About 70% these genes fall into three categories of biological process or function: structural molecule, catalytic activity or transcription regulatory activity. In‐depth analysis of the genes will assist with understanding not only XLID but also cognitive function and brain function in general.

Key Concepts

  • XLID conditions can be partitioned into two broad categories: syndromal and nonsyndromal
  • Molecular analysis allows for splitting XLID conditions thought to be similar
  • Molecular analysis allows for determining distinct XLID entities are allelic
  • XLID proteins fall into 3–4 major categories of function
  • Better understanding of XLID gene function may lead to treatment therapies

Keywords: X‐linked intellectual disability (XLID); nonsyndromal XLID; gene classification; human evolution

Figure 1. Ideogram of X chromosome showing XLID syndromes. The location of the genes for XLID syndromes which have been cloned and mutations demonstrated are indicated with arrows. Syndromes associated with each gene are indicated. Reproduced with permission from Scwartz © Greenwood Genetic Center.
Figure 2. Ideogram of X chromosome showing nonsyndromic XLID genes and families. The locations of the nonsyndromic XLID (MRX) genes which have been cloned are indicated on the left with solid arrows. Genes that cause both syndromic and nonsyndromic XLID are shown on the right with open arrows. Linkage limits for MRX families which have been mapped (lod score >2), but the genes not yet cloned are indicated on the right side of the figure. Numbers indicate the specific nonsyndromic XLID family and the bars represent the region of localisation. Reproduced with permission from Scwartz © Greenwood Genetic Center.
Figure 3. Ideogram of X chromosome showing location of segmental duplications associated with XLID. Reproduced with permission from Scwartz © Greenwood Genetic Center.


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Further Reading

Chelly J, Khelfaoui M, Francis F, Cherif B and Bienvenu T (2006) Genetics and pathophysiology of mental retardation. European Journal of Human Genetics 14: 701–713.

Gécz J, Shoubridge C and Corbett M (2009) The genetic landscape of intellectual disability arising from chromosome X. Trends in Genetics 25: 308–316.

Graves JA, Gecz J and Hameister H (2002) Evolution of the human X‐a smart and sexy chromosome that controls speciation and development. Cytogenetic and Genome Research 99: 141–145.

Laumonnier F, Cuthbert PC and Grant SG (2007) The role of neuronal complexes in human X‐linked brain diseases. American Journal of Human Genetics 80: 205–220.

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Moog U (2005) The outcome of diagnostic studies on the etiology of mental retardation: considerations on the classification of the causes. American Journal of Medical Genetics Part A 137: 228–231.

Ropers HH (2008) Genetics of intellectual disability. Current Opinion in Genetics & Development 18: 241–250.

Skuse DH (2005) X‐linked genes and mental functioning. Human Molecular Genetics 14 (1) Spec No : R27–R32.

Stevenson RE and Schwartz CE (2009) X‐linked intellectual disability: unique vulnerability of the male genome. Developmental Disabilities Research Reviews 15: 361–368.

Stevenson RE, Schwartz CE and Rogers RC (2012) Atlas of X‐linked Intellectual Disability Syndromes. New York: Oxford University Press.

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Schwartz, Charles E(Oct 2015) X‐Linked Intellectual Disability Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006175.pub2]