Severe nonspecific X-linked mental retardation caused by a proximally Xp located gene: intragenic heterogeneity or a new form of X-linked mental retardation?

Abstract

X-linked mental retardation (XLMR) can be subdivided into syndromic and nonsyndromic or nonspecific. Patients with non-syndromal XLMR show no characteristic manifestations, biochemical defects, or distinct fragile sites. Nevertheless, nonspecific XLMR seems to be heterogeneous. To determine the number and location of the genes responsible for XLMR, linkage studies in large pedigrees have to be performed. Here we report the data of linkage analysis in a large Brazilian family with 7 patients affected by a severe form of XLMR, with no other associated malformations. All the obligate carriers are normal. A close linkage without recombination (lod scores 1.95 and 3.25) was found between the disease locus and polymorphic DNA loci DXS255 (Xp11.22), DXS14 (Xp11.21). These results suggest that the gene responsible for the disease in this family maps in the Xp11-cent of the X chromosome. Positive lod scores in this region have also been reported for other XLMR genealogies, but with a much milder phenotype. The possibility of intragenic or locus heterogeneity is discussed.