Genetic localisation of mental retardation with spastic diplegia to the pericentromeric region of the X chromosome: X inactivation in female carriers.

We report on two brothers and one maternal cousin with severe mental retardation, microcephaly, short stature, cryptorchidism, and spastic diplegia. The patients were born to normal and non-consanguineous parents. All other members of the family, almost exclusively females, were clinically normal, suggesting X linked inheritance. By multipoint linkage analysis with markers spanning the whole X chromosome, we have tentatively assigned the underlying genetic defect to Xp11.4-q21, achieving a maximum lod score of 1.3. This localisation overlaps MRXS3, a syndromic form of mental retardation resembling that found in the family described here, although with a milder presentation. We discuss the possibility that both phenotypes might be allelic variants of the same gene localised in the pericentromeric region of the X chromosome. Analysis of the X inactivation pattern in one potential and three obligate carrier females showed non-random inactivation of the allele linked to the disease. This finding may be interpreted as: (1) a negative selection effect on cells bearing the mutation on the active X chromosome; (2) both the disease causing gene and the X inactivation centre are simultaneously affected by the same alteration, a deletion for instance; or (3) the skewed inactivation is the consequence of an independent event randomly associated with the disease. In any case, the observation of consistent X inactivation supports X linkage of the disease.