RT Journal Article
SR Electronic
T1 Genetic localisation of mental retardation with spastic diplegia to the pericentromeric region of the X chromosome: X inactivation in female carriers.
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 284
OP 287
DO 10.1136/jmg.35.4.284
VO 35
IS 4
A1 F Martínez
A1 M Tomás
A1 J M Millán
A1 A Fernández
A1 F Palau
A1 F Prieto
YR 1998
UL http://jmg.bmj.com/content/35/4/284.abstract
AB 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.