Mental Retardation, X-Linked 46

Clinical Features

Yntema et al. (1998) reported a large Dutch family in which 12 males in 3 generations were affected with nonspecific X-linked mental retardation. Of 9 examined patients, 6 showed moderate mental retardation, and 1 each showed mild, severe, and profound mental retardation. Obligate female carriers were all normal.

Mapping

Linkage analysis of the family reported by Yntema et al. (1998) yielded a maximum lod score of 5.12 at HPRT between DXS8072 and DXS294 at Xq25-q26.

Cytogenetics

Kutsche et al. (2000) studied a male patient with severe mental retardation, mildly dysmorphic features, and sensorineural hearing loss who carried an apparently balanced X;21 translocation with breakpoints in Xq26 and 21p11. His unaffected mother carried the same translocation (von Ballestrem et al., 1996). Molecular analysis showed that the ARHGEF6 gene was disrupted by the rearrangement. Kutsche et al. (2000) detected wildtype ARHGEF6 mRNA in the patient's mother. This was unusual because in most females with a balanced X/autosome translocation, the normal X chromosome is preferentially inactivated. This finding, however, was consistent with the mother's normal phenotype. Somatic cell hybrid studies indicated that the ARHGEF6 gene does not escape X inactivation. Further studies indicated that the translocation was reciprocal but molecularly unbalanced, with a 10-bp deletion on the X chromosome and a 9-bp deletion in the beta-satellite DNA on chromosome 21.

Molecular Genetics

Exclusion Studies

The variant in the ARHGEF6 gene identified by Kutsche et al. (2000) in affected members of the family with X-linked mental retardation described by Yntema et al. (1998) has been reclassified as a variant of unknown significance; see 300267.0001.