X-linked mental retardation

Key Points X-linked genetic defects are important causes of mental retardation, and recent years have seen important progress in the identification of the genes involved in X-linked mental retardation (XLMR). There are two main forms of XLMR — syndromic XLMR (S-XLMR), which is associated with additional phenotypes, and non-syndromic XLMR (NS-XLMR). Whereas most of the genetic defects that underlie S-XLMR are either known or have been mapped to small chromosomal regions, fewer than 50% of those that underlie NS-XLMR have been identified. Genes that are involved in S-XLMR can be identified using standard techniques for identifying genes involved in monogenic disorders. However, it is not as straightforward for NS-XLMR, mainly because of the genetic heterogeneity of this condition. Recent years have seen concerted efforts to identify genes that are involved in XLMR. Studies of chromosomal rearrangements, the availability of large numbers of families for genetic analysis and large-scale mutational screening have all been important in this work. The identification of XLMR-associated genes has provided insights into brain function. The genes that are affected in these conditions have roles in processes such as neuronal outgrowth, synaptic structure and function, synaptic plasticity and learning and memory, and might also be determinants of intelligence. Polymorphisms that predispose to mental retardation — but are not sufficient to cause symptoms on their own — might be present within the protein-coding regions of genes, their regulatory regions or in genes that encode small regulatory RNAs. Allelic variants of genes that are involved in XLMR might be candidates for such polymorphisms. Understanding the genetic causes of XLMR will be important in developing diagnostic, preventive and therapeutic strategies for the treatment and management of this condition. Genetic factors have an important role in the aetiology of mental retardation. However, their contribution is often underestimated because in developed countries, severely affected patients are mainly sporadic cases and familial cases are rare. X-chromosomal mental retardation is the exception to this rule, and this is one of the reasons why research into the genetic and molecular causes of mental retardation has focused almost entirely on the X-chromosome. Here, we review the remarkable recent progress in this field, its promise for understanding neural function, learning and memory, and the implications of