Mental Retardation, Autosomal Dominant 42

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-42 (MRD42) is caused by heterozygous mutation in the GNB1 gene (139380) on chromosome 1p36.

Description

Autosomal dominant mental retardation-42 is a neurodevelopmental disorder characterized by global developmental delay and intellectual disability. More variable features include hypotonia, often later associated with limb hypertonia, seizures of various types, and poor overall growth. Strabismus, cortical visual impairment, and autistic features may also be present (summary by Petrovski et al., 2016).

Clinical Features

Petrovski et al. (2016) reported 13 unrelated individuals, ranging in age from 13 months to 20 years, with global developmental delay. Additional common, but somewhat variable, features included hypotonia (11 patients), seizures (10 patients), and poor overall growth without microcephaly. Hypotonia varied in severity: 3 patients were unable to ambulate and 4 developed limb hypertonia. Seizures types included focal, generalized, myoclonic, atonic, tonic, absence, and complex partial, and the age at seizure onset ranged from infancy to 11 years. EEG patterns were variable, with generalized slowing and multifocal spikes; some patients showed hypsarrhythmia. Eight patients had variable ophthalmologic abnormalities, including strabismus, nystagmus, slow ocular pursuit, and cortical visual impairment. A few patients had autism spectrum disorder or attention deficit-hyperactivity disorder, and 2 had hydronephrosis. Some had mild dysmorphic features, such as cleft palate, but there was no recognizable gestalt. Brain imaging was normal in most patients, but 1 patient had polymicrogyria and delayed myelination.

Molecular Genetics

In 13 unrelated patients with MRD42, Petrovski et al. (2016) identified 9 different de novo heterozygous missense mutations in the GNB1 gene (see, e.g., 139380.0001-139380.0005). The mutations were identified by exome sequencing and confirmed by Sanger sequencing. The patients were ascertained from a cohort of 5,855 individuals with a presumed genetic disorder of unknown cause. Functional studies and studies of patient cells were not performed by Petrovski et al. (2016). However, Petrovski et al. (2016) noted that Yoda et al. (2015) had identified somatic mutations in the GNB1 gene that were associated with hematologic transformation. Functional studies of 3 of the mutations (D76G, 139380.0001; I80T, 139380.0002; I80N, 139380.0003) that were also identified as germline mutations in the patients reported by Petrovski et al. (2016) had reduced binding to almost all G-alpha subunits and/or conferred cytokine-independent growth and activation of canonical G protein downstream signaling through disruption of the G-alpha/G-beta/G-gamma interaction interface. The mutations resulted in activation of the PI3K-AKT-mTOR and MAPK pathways, consistent with a gain of function.