Mental Retardation, X-Linked 12

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-12 (MRX12) is caused by mutation in the THOC2 gene (300395) on Xq25.

Clinical Features

Kumar et al. (2015) reported 4 unrelated families with X-linked mental retardation. Two of the families had previously been reported by Kerr et al. (1992) as 'MRX12' and by Gu et al. (1996) as 'MRX35.' All 20 males in the study of Kumar et al. (2015) had intellectual disability that ranged from borderline to severe. Common additional features included speech delay, short stature, elevated body mass index (BMI), and a truncal obesity pattern in older males. There were variable neurologic features, including hypotonia, tremor, gait disturbances, and behavioral problems. Five patients had seizure disorders. Neuroradiologic findings performed in only a few patients showed mild ventriculomegaly, gliosis, inferior cerebellar vermis dysplasia, and cervical cord compression. Less common clinical features included microcephaly and microorchidism and/or microphallus. Although some patients had dysmorphic facial features, there was no common pattern. One carrier female had borderline-mild intellectual disability.

Inheritance

The transmission pattern of mental retardation in the families reported by Kumar et al. (2015) was consistent with X-linked recessive inheritance.

Molecular Genetics

In affected members of 4 unrelated families with X-linked mental retardation, Kumar et al. (2015) identified 4 different hemizygous missense mutations in the THOC2 gene (300395.0001-300395.0004). The mutations, which were found by X-chromosome exome sequencing, segregated with the disorder in the respective families. Studies of patient-derived cells showed that 2 of the variants resulted in decreased stability of THOC2 and its TREX-complex partners; however, no changes were observed in cells derived from the other 2 variants. Kumar et al. (2015) concluded that all the variants resulted in a partial loss of function and alterations in mRNA export, which likely impaired protein synthesis. The findings suggested that THOC2 and nuclear mRNA-export are crucial factors for proper neuronal development.