Mental Retardation, Autosomal Dominant 24

A number sign (#) is used with this entry because autosomal dominant mental retardation-24 (MRD24) is caused by heterozygous mutation in the DEAF1 gene (602635) on chromosome 11p15.

Clinical Features

Vulto-van Silfhout et al. (2014) reported 4 unrelated children with MRD24, including 2 patients previously identified by Vissers et al. (2010) and Rauch et al. (2012). All patients had delayed psychomotor development with absent or very poor expressive speech and gait abnormalities. Three had poor eye contact. Dysmorphic features were mild, but included thin and/or fair hair, straight eyebrows, full nasal tip, tented upper lip, full lower lip, and prominent chin. Three patients had skin syndactyly of toes 2-3, 2 had a sacral dimple, and 2 had hyperlaxity. All also had recurrent infections and a high pain threshold. The patients were described as having a happy disposition, but 3 had severe behavioral abnormalities consisting of autistic, compulsive, hyperactive, and aggressive behavior with striking mood swings.

Molecular Genetics

In 1 of 10 patients with mental retardation, Vissers et al. (2010) identified a de novo heterozygous missense mutation in the DEAF1 gene (I228S; 602635.0001). The mutation was found by exome sequencing. In a girl with nonsyndromic intellectual disability, Rauch et al. (2012) identified a de novo heterozygous missense mutation in the DEAF1 gene (Q264P; 602635.0002). The patient was ascertained from a large cohort of 51 patients with intellectual disability who underwent exome sequencing.

In 2 unrelated patients with MRD24, Vulto-van Silfhout et al. (2014) identified 2 different missense mutations in the DEAF1 gene (R224W, 602635.0003 and R254S, 602635.0004). The patients were ascertained from a cohort of over 2,300 individuals with intellectual disability who underwent targeted resequencing of the DEAF1 gene. In vitro functional expression assays using a luciferase reporter indicated that all 4 of the mutations, including those reported by Vissers et al. (2010) and Rauch et al. (2012), resulted in a loss of the ability of DEAF1 to repress its own promoter, and all mutations produced proteins with loss of or significantly reduced DNA binding. Three of the mutations caused a loss of transcriptional activity. Compared to the other mutations, the R254S mutation resulted in less severe defects and enabled some residual DEAF1 activity. Vulto-van Silfhout et al. (2014) postulated a dominant-negative effect of the mutations. One of the patients also carried a heterozygous c.1570C-T transition in the SCN2A gene (182390), resulting in an arg524-to-ter (R524X) substitution, which may have influenced the severity of the intellectual disability; however, the patient did not have a history of epilepsy.

Animal Model

Vulto-van Silfhout et al. (2014) found that homozygous knockout of the Deaf1 gene was lethal in mice. Transgenic mice with conditional homozygous knockdown of the Deaf1 gene in brain showed increased anxiety-related behavior in field tests as well as impaired contextual memory.