A unique form of mental retardation with a distinctive phenotype maps to Xq26-q27

We report a novel X-linked mental retardation (XLMR) syndrome, with charact eristic facial dysmorphic features, segregating in a large North Carolina f amily. Only males are affected, over four generations. Clinical findings in the seven living affected males include a moderate degree of mental retard ation (MR), coarse facies, puffy eyelids, narrow palpebral fissures, promin ent supraorbital ridges, a bulbous nose, a prominent lower lip, large ears, obesity, and large testicles. Cephalometric measurements suggest that the affected males have a distinctive craniofacial skeletal structure, when com pared with normative measures. Obligate-carrier females are unaffected with MR, but the results of cephalometric skeletal analysis suggest craniofacia l dysmorphisms intermediate between affected males and normative control in dividuals. Unaffected male relatives show no clinical or cephalometric rese mblance to affected males. The blood-lymphocyte karyotype and the results o f DNA analysis for fragile-X syndrome and of other routine investigations a re normal. Linkage analysis for polymorphic DNA markers spanning the X chro mosome established linkage to Xq26-q27. Maximum LOD scores were obtained at marker DXS1047 (maximum LOD score = 3.1 at recombination fraction 0). By u se of haplotype analysis, we have localized the gene for this condition to an 18-cM genetic interval flanked by ATA59C05 and GATA31E08. On the basis o f both the clinical phenotype and the mapping data, we were able to exclude other reported XLMR conditions. Therefore, we believe that a unique recess ive XLMR syndrome with a distinctive and recognizable phenotype is represen ted in this family.