Monogenic causes of X-linked mental retardation

Abstract

Mental retardation, as reflected by impaired cognitive function, is the most common cause of handicap in children and young adults. Its underlying causes are heterogeneous, and include genetic and environmental factors. Many disease genes associated with mental retardation have been identified in recent years. Impaired cognitive function is seen in monogenic metabolic and developmental disorders, and as a result of chromosomal rearrangements. Mental retardation has a 20–30% higher incidence in males than in females, indicating that some forms of the disorder are X linked. Work on syndromic and nonspecific forms of X-linked mental retardation (XLMR) are beginning to identify causative mutations in X-linked genes. Disease genes have recently been identified in three syndromic forms of XLMR: ATRX, Coffin–Lowry and Rett syndromes. The genes affected in these diseases are all believed to be involved in chromatin remodelling, providing an important insight into a cellular process that might be perturbed in individuals with mental retardation. Nonspecific forms of XLMR are a greater challenge to study owing to their clinical and genetic heterogeneity, but recent progress in this area has been made. Mutations have been found in several genes that act in signal transduction pathways in neuronal cells in patients with nonspecific XLMR. Some of these mutations are likely to alter cytoskeletal dynamics and neuronal morphogenesis. Genes that are involved in syndromic XLMR have also been found to be mutated in nonspecific forms of the disorder. The pooling of clinical and genetic resources, and new sequence data, are likely to lead to further discoveries of genes involved in mental retardation, both on the X chromosome and autosomes. How these findings can be applied diagnostically, however, remains an open question, given the difficulty of screening some of the larger genes involved in mental retardation and the clinical heterogeneity of some of the disorders.