X-linked mental retardation syndrome with characteristic "coarse" facial appearance, brachydactyly, and short stature maps to proximal Xq

We describe a three-generation family in which X-linked mental retardation (XLMR) is associated with minor facial anomalies and brachydactyly. Two bro thers and four nephews have "coarse" facial appearance, brachydactyly with widening of the distal phalanges, short stature, and moderate mental retard ation. The three obligate carrier women have normal intelligence and normal physical findings. The results of linkage analysis carried out in 1988 usi ng restriction fragment length polymorphisms (RFLPs) were suggestive of lin kage to DXYS1 and DXS101 in proximal Xq (Z(max) = 1.63 at theta(max) = 0.0) [Carpenter et al., 1988: Am J Med Genet 43:A139]. The family was restudied with 16 microsatellite loci from Xp11.4 through Xq24. Linkage analysis dem onstrated significant linkage to DXS1003, ALAS2, AR, DXS986, DXS990, DXS454 , DXS1106, DXS1105, and DXS1220 from Xp11.3 to Xq23 (Z(max) = 2.53 at theta (max) = 0.0). Recombinations detected between MAOB and DXS1055 and between DXS1220 and DXS1001 place the disease locus between Xp11.3 and Xq23; Among the genes known to map to this region is the XNP gene for the alpha-thalass emia/mental retardation syndrome (ATR-X). This fact, along with the phenoty pic similarity between our patients and ATR-X males, led us to consider XNP as a candidate gene for this family. X-inactivation studies provided furth er evidence for the involvement of XNP by showing completely skewed X-inact ivation patterns in the three obligate carrier females, a pattern character istic of carriers of XNP mutations. Am. J. Med. Genet. 85:230-235, 1999.