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

Abstract

We report a novel X-linked mental retardation (XLMR) syndrome, with characteristic facial dysmorphic features, segregating in a large North Carolina family. Only males are affected, over four generations. Clinical findings in the seven living affected males include a moderate degree of mental retardation (MR), coarse facies, puffy eyelids, narrow palpebral fissures, prominent 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 compared with normative measures. Obligate-carrier females are unaffected with MR, but the results of cephalometric skeletal analysis suggest craniofacial dysmorphisms intermediate between affected males and normative control individuals. Unaffected male relatives show no clinical or cephalometric resemblance to affected males. The blood-lymphocyte karyotype and the results of DNA analysis for fragile-X syndrome and of other routine investigations are normal. Linkage analysis for polymorphic DNA markers spanning the X chromosome established linkage to Xq26-q27. Maximum LOD scores were obtained at marker DXS1047 (maximum LOD score = 3.1 at recombination fraction 0). By use 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 of both the clinical phenotype and the mapping data, we were able to exclude other reported XLMR conditions. Therefore, we believe that a unique recessive XLMR syndrome with a distinctive and recognizable phenotype is represented in this family.

Figure 1

Pedigree of the family, showing an X-linked recessive mode of inheritance and the haplotypes of the members studied. The consultand is indicated by the arrow. Genetic-map distances are derived from the female chromosome X genetic map.

Figure 2

Composite picture of affected males, showing characteristic facial features. In order, these males are individuals III-2 (A), IV-3 (B), IV-4 (C), IV-5 (D), IV-6 (E), IV-9 (F), V-3 (G), and V-4 (H). Individual IV-9 is deceased. Individual III-2 has recently lost >100 lbs., as a result of dietary restrictions required because of diabetes mellitus.

Figure 3

Photo of unaffected male (individual IV-10), illustrating lack of resemblance to the affected males.

Figure 4

Composite picture of cephalometric measurements in affected males IV-3 and IV-5 (A and B, respectively), showing vertical mandibular angle, in comparison with that in unaffected male IV-10 (D). The mandibular angle in carrier female III-1 (C) is between that of the affected males and that of the unaffected male. Note the lip protrusion in the affected males.

Figure 5

Schematic localization of a unique XLMR syndrome, as implied by the current report, in relation to other reported XLMR conditions in close proximity. Vertical arrows indicate DNA markers tested in the present study. Asterisks (*) indicate markers that have previously been linked to other XLMR conditions. Mutations within the GPC3 gene have been found in SBGS. CS = Cowchock syndrome, GS = Gustavson syndrome, SG = SGBS , XPH = X-linked recessive panhypopituitarism, MR-IGHD = mental retardation with isolated growth hormone deficiency, and MRX = nonspecific XLMR.