Mental Retardation, Autosomal Dominant 45

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-45 (MRD45) is caused by heterozygous mutation in the CIC gene (612082) on chromosome 19q13.

Clinical Features

Lu et al. (2017) reported 5 patients from 4 families with a neurodevelopmental disorder characterized by delayed development apparent in infancy or the first years of life, variable intellectual disability, often with language delay, and behavioral disorders, including autistic features, attention deficit, and hyperactivity. Some patients showed developmental regression early in life and/or learning difficulties. Three patients had seizures, including blinking and staring episodes, myoclonic seizures, complex partial seizures, and absence seizures. Two patients had hypotonia, and 3 had nonspecific T2-weighted white matter abnormalities on brain imaging.

Molecular Genetics

In 5 patients from 4 unrelated families with MRD45, Lu et al. (2017) identified 4 different heterozygous truncating or frameshift mutations in the CIC gene (612082.0001-612082.0004). All mutations occurred de novo, although 2 affected sibs likely inherited the mutation from an unaffected parent who was gonadal mosaic, and another patient inherited the mutation from his unaffected father who was mosaic for the mutant allele. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Cells derived from 1 patient showed a 50% decrease in mRNA and protein levels, consistent with haploinsufficiency.

In a boy with MRD45, Vissers et al. (2010) identified a heterozygous de novo missense mutation (R292W; 612082.0005) in the CIC gene.

Animal Model

Lu et al. (2017) found that conditional knockdown of the Cic gene in the mouse developing forebrain caused learning and memory deficits and hyperactivity that responded to low-dose amphetamine. Conditional knockout mice had decreased cortical thickness of layers 2 to 4, apparently due to increased apoptosis, as well as decreased dendritic branching compared to controls. These changes were associated with a decrease in Cux1 (116896) levels. Cortical layers 5 and 6 did not have decreased thickness, but there was decreased thickness of the hippocampal dentate gyrus. The overall findings suggested a defect in postnatal maturation or maintenance of upper-layer cortical neurons.