Mental Retardation, X-Linked 107

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-107 (MRX107) is caused by hemi- or heterozygous mutation in the CXORF56 gene (301012) on chromosome Xq24. One such family has been reported.

Clinical Features

Verkerk et al. (2018) reported a large 3-generation Dutch family in which 5 males and 1 female had mild to moderate intellectual disability. The patients had delayed development but were able to attend special schools, and some were able to work in a sheltered environment. Two males had significant behavioral problems, such as pervasive developmental disorder, attention disorder, hyperactivity, and transgressive behavior. The patients had variable dysmorphic facial features, including long, narrow face, prominent chin, upward slanting palpebral fissures, flat philtrum, narrow upper lip, and large ears with prominent cruxes.

Inheritance

The transmission pattern of mental retardation in the family reported by Verkerk et al. (2018) was consistent with X-linked inheritance with decreased penetrance in females.

Molecular Genetics

In 5 affected males and 1 affected female from a large multigenerational Dutch family with MRX107, Verkerk et al. (2018) identified a hemi- or heterozygous frameshift mutation in the CXORF56 gene (301012.0001). The mutation, which was found by a combination of linkage analysis and whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. X-chromosome inactivation studies showed that the carrier females had skewed inactivation (76-93%) of the variant allele, whereas the affected female did not have a skewed X-inactivation pattern, suggesting that her levels of the mutant mRNA were higher than those in the unaffected females. Analysis of patient cells showed evidence of nonsense-mediated mRNA decay and decreased levels of the mutant mRNA compared to controls. The findings suggested a loss-of-function effect.