Mental Retardation, X-Linked 45

Clinical Features

Hamel et al. (1999) described a 6-generation family segregating X-linked mental retardation. Affected members demonstrated nonprogressive mental retardation during childhood and had large, simple ears, relatively large hands, and normal behavior. The propositus also had clinodactyly of the fifth fingers and flat feet; findings in other affected individuals included short stature, high-arched palate, high nasal bridge, full lips, and large testes. The mental retardation in family MRX45 ranged from mild to severe: most affected members showed higher adaptive than intellectual functioning, and most could read, write, and solve simple arithmetic problems.

Cytogenetics

In a female patient with severe mental retardation and a de novo translocation t(X;9)(p11.23;q34.3), Kleefstra et al. (2004) characterized the breakpoints and found that the translocation disrupted the ZNF81 gene.

Mapping

Hamel et al. (1999) performed linkage analysis in family MRX45 and obtained a maximum lod score of 3.99 (theta = 0.0) with marker DXS337. Using haplotype construction, they narrowed the region of linkage to Xp11.3-p11.21 in a 10-cM interval flanked by markers DXS1003 and ALAS2.

Molecular Genetics

Kleefstra et al. (2004) performed mutation analysis in over 300 families and patients with nonspecific X-linked mental retardation and identified a ser179-to-asn mutation in the ZNF81 gene (314998.0001) in affected members of the MRX45 family reported by Hamel et al. (1999). Hamosh (2017) noted that the S179N variant was found in 4 males and in 8 of 81,134 alleles in the ExAC database (February 22, 2017), suggesting that the variant is not pathogenic.