Mental Retardation, X-Linked, Syndromic 11

A number sign (#) is used with this entry because of evidence that X-linked syndromic mental retardation-11 (MRXS11) is caused by mutation in the RBMX gene (300199) on chromosome Xq26. One such family has been reported.

Clinical Features

In a large family from North Carolina, Shashi et al. (2000) studied a seemingly novel X-linked mental retardation syndrome with characteristic facial dysmorphic features. Only males were affected over 4 generations. Clinical findings in the 7 living affected males included a moderate degree of mental retardation, coarse facies, puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges, a bulbous nose, prominent lower lip, large ears, obesity, and large testes. Cephalometric measurements suggested that the affected males had a distinctive craniofacial skeletal structure, when compared with normative measurements. Obligate-carrier females had no mental retardation, but the results of cephalometric analysis suggested craniofacial dysmorphism intermediate between that of affected males and that of normative control individuals. Unaffected male relatives showed no clinical or cephalometric resemblance to affected males. The blood-lymphocyte karyotype and the results of DNA analysis for fragile X syndrome (300624) and of other routine investigations were normal.

Shashi et al. (2015) provided follow-up of the family reported by Shashi et al. (2000). One of the original affected individuals died of age-related complications in his eighties, and an additional 13-year-old male family member had features consistent with the disorder. Four affected individuals developed bilateral sensorineural hearing loss in their early fifties.

Mapping

By linkage analysis with polymorphic DNA markers spanning the X chromosome in a large family with an X-linked mental retardation syndrome, Shashi et al. (2000) established linkage to Xq26-q27. A maximum lod score of 3.1 was obtained at marker DXS1047 (recombination fraction of 0.0). Shashi et al. (2000) concluded that the features in this family were not consistent with those seen in any previously delineated forms of X-linked mental retardation, including those with a similar phenotype and those that had been mapped in close proximity.

Genetic Heterogeneity

Castro et al. (2003) described a family with mental retardation in 2 brothers. The pedigree was consistent with either X-linked mental retardation or autosomal recessive inheritance. The diagnosis of Shashi X-linked mental retardation syndrome was suggested by the clinical features of coarse facies, prominent lower lip, large testes, and obesity. Haplotype analysis in the family with mental retardation described by Castro et al. (2003) was consistent with the localization of Shashi X-linked mental retardation syndrome to chromosome Xq26-q27. Castro et al. (2003) concluded that the family represented a second occurrence of Shashi X-linked mental retardation. Shashi et al. (2015) performed Sanger sequencing of the RBMX gene in the brothers reported by Castro et al. (2003) and did not identify any pathogenic variants, suggesting that these patients have a different disorder.

Molecular Genetics

In all affected males from a family with MRXS11 originally reported by Shashi et al. (2000), Shashi et al. (2015) identified a hemizygous truncating mutation in the RBMX gene (300199.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies and studies on patient cells were not performed.