title: Genetic localisation of mental retardation with spastic diplegia to the pericentromeric region of the X chromosome: X inactivation in female carriers.
abstract: 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.
authors.affiliation: Unidad de Genética, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Martínez
authors.forename: M
authors.initials: M
authors.lastname: Tomás
authors.forename: J M
authors.initials: JM
authors.lastname: Millán
authors.forename: A
authors.initials: A
authors.lastname: Fernández
authors.forename: F
authors.initials: F
authors.lastname: Palau
authors.forename: F
authors.initials: F
authors.lastname: Prieto
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D002503:Centromere; D002547:Cerebral Palsy / Q000235:genetics*; D002648:Child; D002874:Chromosome Mapping; D004303:Dosage Compensation, Genetic; D005260:Female; D008040:Genetic Linkage; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D010375:Pedigree; D014960:X Chromosome