Mental Retardation, Autosomal Dominant 48

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-48 (MRD48) is caused by heterozygous mutation in the RAC1 gene (602048) on chromosome 7p22.

Clinical Features

Reijnders et al. (2017) reported 7 unrelated boys, ranging from 4.5 months to 15 years of age, with global developmental delay and moderate to severe intellectual disability. The phenotype was highly variable: 1 patient had an IQ of 35 at age 13, several had poor or absent speech, and several had delayed or impaired walking. Other neurologic features included poor feeding, hypotonia (in 4 patients), seizures (3), behavioral problems (3), and stereotypical movements (3). Four patients had microcephaly (-2.5 to -5 SD), 1 was normocephalic, and 2 had macrocephaly (+4.16 and +4.5 SD). Most patients had dysmorphic facial features, although there was not a common recognizable gestalt. Features included arched eyebrows, dysplastic ears, prominent nasal bridge, upturned nose, overhanging columella, long palpebral fissures, and broad or open mouth. One patient had sensorineural hearing loss and mild visual impairment. Brain imaging was abnormal in all 6 patients who were studied, although these findings were also highly variable. Common abnormalities included cerebellar hypoplasia, cerebellar dysplasia, hypoplasia of the corpus callosum, enlarged ventricles, mega cisterna magna, and thin brainstem. One patient had polymicrogyria. The 2 patients with macrocephaly had only nonspecific periventricular white matter lesions. Other less common extraneurologic features included hypospadias, cardiac abnormalities, recurrent infections, and eczema.

Molecular Genetics

In 7 unrelated boys with MRD48, Reijnders et al. (2017) identified 7 different de novo heterozygous missense mutations in the RAC1 gene (see, e.g., 602048.0001-602048.0006). The mutations were found by whole-exome sequencing, and the patients were ascertained from several different research studies and the GeneMatcher database. In vitro functional expression studies of selected variants showed different effects: 2 mutations (C18Y, 602048.0001 and N39S, 602048.0002) had a dominant-negative effect on fibroblast spreading and caused reduced neuronal proliferation and cerebellar abnormalities in a zebrafish model, whereas 1 mutation (Y64D; 602048.0004) resulted in constitutive activation of RAC1. The other mutations appeared to have lesser and unclear effects on RAC1 function. Reijnders et al. (2017) noted that the large phenotypic variability among patients may represent mutation-specific effects.