A GENE FOR DOMINANT NONSPECIFIC X-LINKED MENTAL-RETARDATION IS LOCATED IN XQ28

A large family (MRX48) with a nonspecific X-linked mental retardation condition is described. An X-linked semidominant inheritance is sugges ted by the segregation in three generations of a moderate to severe me ntal retardation in seven males and by a milder intellectual impairmen t in two females, without any specific clinical, radiological, or biol ogical feature. Two-point linkage analysis demonstrated significant li nkage between the disorder and several markers in Xq28 (maximum LOD sc ore [Z(max)] = 2.71 at recombination fraction [theta] = 0); multipoint linkage analyses confirmed the significant linkage with a Z(max) of 3 .3 at theta = 0, at DXS1684. A recombination event observed with the f lanking marker DXS8011 delineates a locus between this marker and the telomere. The approximate length of this locus is 8-9 cM, correspondin g to 5.5-6 Mb. In an attempt to explain the variable intellectual impa irment in females, we examined X-chromosome inactivation in all female s of the family. Inactivation patterns in lymphocytes were random or m oderately skewed, and no correlation between the phenotypic status and a specific inactivation pattern was observed. The interval of assignm ent noted in this family overlaps with five MRX loci previously report ed in Xq28.