Mental Retardation, X-Linked 41

A number sign (#) is used with this entry because this form of X-linked mental retardation, referred to as MRX41 or MRX48, is caused by mutation in the GDI1 gene (300104) on chromosome Xq28.

Clinical Features

Hamel et al. (1996) reported a family segregating mild to moderate mental retardation as an X-linked trait (MRX41).

Des Portes et al. (1997) reported a large 3-generation family segregating nonspecific X-linked mental retardation (MRX48). The pedigree suggested X-linked semidominant inheritance: moderate to severe mental retardation was found in 7 males and milder intellectual impairment in 2 females, without any specific clinical, radiologic, or biologic features.

Bienvenu et al. (1998) reported a large French family (family R) in which all affected males showed moderate to severe mental retardation. X-linked semidominant inheritance was strongly suggested by the severe phenotypes in males in comparison to mildly affected females or unaffected obligate carriers. The study suggested that the prevalence of GDI1 mutations in nonspecific mental retardation may be 0.5 to 1%.

Strobl-Wildemann et al. (2011) reported a multigenerational German family in which 9 males had nonsyndromic X-linked mental retardation. The proband was noted to have absence seizures at age 12, a small pointed chin, and crowded teeth, but no other dysmorphic features were noted and no other patients had dysmorphic features. Two of 4 female carriers had learning disabilities, and 1 also had attention-deficit disorder. Strobl-Wildemann et al. (2011) noted the lack of specific features that could alert the clinician to this form of mental retardation.

Mapping

By 2-point linkage analysis in a family segregating nonspecific X-linked mental retardation (MRX41), Hamel et al. (1996) demonstrated linkage of the disorder to marker DXS3 at Xq21.33 with a lod score of 2.56 at theta = 0.0 and marker DXS1108 at Xq28 with a lod score of 3.82 at theta = 0.0. Multipoint linkage analysis showed that the odds for a location of the locus at Xq28 versus Xq21.33 were 100:1.

In a large 3-generation French family segregating nonspecific X-linked mental retardation (MRX48), des Portes et al. (1997) found linkage of the disorder to DXS1684 with a maximum lod of 3.0 at theta = 0.0. The authors commented that the mapping overlapped with that of MRX3 (309541) and 4 other X-linked mental retardation families: MRX16 (300055); MRX25, reported by Nordstrom et al. (1992); MRX28, reported by Holinski-Feder et al. (1996); and MRX41, reported by Hamel et al. (1996). Intervals of assignment in these 6 families were within the 6-Mb telomeric region of the X chromosome and they could represent allelic disorders.

Molecular Genetics

D'Adamo et al. (1997, 1998) demonstrated unique mutations in the RABGDIA gene in affected members of the MRX41 family (300104.0001) reported by Hamel et al. (1996) and the MRX48 family (300104.0002) reported by des Portes et al. (1997).

Bienvenu et al. (1998) carried out mutation screening of the whole coding region of the GDI1 gene, using a combination of denaturing gradient gel electrophoresis and direct sequencing, in 164 patients found negative for expansions across the FRAXA GCC repeat (309550.0004). The authors identified a novel missense mutation in exon 11 of the GDI1 gene (300104.0003) in a French family (family R) with nonspecific mental retardation.

In affected members of a multigenerational German family with nonsyndromic X-linked mental retardation, Strobl-Wildemann et al. (2011) identified a truncating mutation in the GDI1 gene (300104.0004).