Mutations in most of more than 20 known genes causing nonspecific form of X-linked MR (MRX) are very rare and may account for less than 0.5-1% of MR. Linkage studies in extended pedigrees followed by mutational analysis of known MRX genes in the linked interval are often the only way to identify a genetic cause of the disorder.
The 13 MRX genes identified to date account for less than one-fifth of all MRX, suggesting that numerous gene defects cause the disorder in other families.
On the other hand, given the considerable genetic heterogeneity in MRX, one should be extremely cautious in using interfamilial linkage data to narrow down the localisation of MRX genes.
As skewed X-inactivation, an apparently constant feature in FACL4 carrier females was not observed in an obligate carrier belonging to the MRX family presented here, the PAK3 gene should be considered as the strongest candidate for this MRX locus.
Affected individuals in a multiplex pedigree with MRX (MRX30), previously mapped to Xq22, show a point mutation in the PAK3 (p21-activated kinase) gene, which encodes a serine-threonine kinase.
A third MRX family (MRX68) is the result of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene: proposal of a rapid enzymatic assay for screening mentally retarded patients.
Mutations of the gene coding for PAK3 (p21-activated kinase 3) are associated with X-linked, nonsyndromic forms of mental retardation (MRX) in which the only distinctive clinical feature is the cognitive deficit.
Several MRX families mapping to Xq28 were subsequently tested for MECP2 and a causative mutation was discovered in three families, suggesting that it could be one of the main genes involved in MRX.
Moreover, screening of a panel of patients with MRX led to the identification of two other ZNF41 mutations that were not found in healthy control individuals.