[Non-specific X-linked mental retardation]

Non-specific mental retardation is defined by the absence of somatic, neurological, biochemical or behavioural features that characterise a particular clinical variant and accounts for a large percentage of cases of X-linked mental retardation (XLMR). Genetic linkage studies showed it to have a high rate of genetic heterogeneity.

To date, genetic linkage studies or the characterisation of chromosomal rearrangement in patients have allowed 22 different genes to be identified. Some of the most notable of these are the genes responsible for syndromic forms, such as RPS6KA3, ARX, JARID1C, XNP or MeCP2, in which the mildest mutations, with a certain amount of functional activity, cause non-specific retardation. The proteins these genes code for are directly or indirectly involved in regulating the expression of other genes. Moreover, genes such as OPHN1, PAK3, ARHGEF6, FGD1 or TM4SF2 code for proteins that interact with rho GTPases, and play a role in the transmission of signals that regulate the development of axons and dendrites. Other types of functions of the known genes include establishing and modulating synapses (DLG3, IL1RAPL, NLGN4X, GDI1), regulating transcription (ZNF41, ZNF81, PQBP1) translation (FTSJ1), and fatty acid metabolism (FACL4), etc.

Each gene that has been identified only accounts for a minor fraction of the total amount of XLMR, and even if taken together they still do not explain half the cases of non-specific XLMR. The number of XLMR genes is expected to rise in coming years with the development of new techniques that will facilitate diagnosis and genetic counselling in the relatively near future.