Dyskinesia, Seizures, And Intellectual Developmental Disorder

A number sign (#) is used with this entry because of evidence that dyskinesia, seizures, and intellectual developmental disorder (DYSEIDD) is caused by homozygous mutation in the DEAF1 gene (602635) on chromosome 11p15. One such family has been reported.

Clinical Features

Rajab et al. (2015) reported 3 sibs, born of consanguineous Omani parents, with a neurodevelopmental disorder characterized by severely delayed psychomotor development, intellectual disability, absence of speech, and hypotonia since infancy. At ages 20, 17, and 4, all needed help for basic daily activities. The 2 older sibs developed seizures at age 4 and 2 years, respectively, and one of them had repeated episodes of status epilepticus. The youngest sib did not have seizures at age 4 years, but EEG showed focal epileptic activity. Brain imaging of the 2 older patients showed bilateral T2-weighted hyperintensities in the putamen without leukodystrophic changes or abnormal gyration. The patients also had behavioral abnormalities, including autistic features, mood swings, agitation, and aggression, as well as features reminiscent of Rett syndrome (312750), such as involuntary body and facial movements, drooling, and sleep disturbances.

Inheritance

The transmission pattern of DYSEIDD in the family reported by Rajab et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 sibs, born of consanguineous Omani parents, with DYSEIDD, Rajab et al. (2015) identified a homozygous splice site mutation in the DEAF1 gene (602635.0006). The mutation was found by a combination of linkage analysis and whole-exome sequencing and was confirmed by Sanger sequencing. It segregated with the disorder in the family. The mutation was verified to cause a splicing defect and about 80% mRNA decay, leaving only about 4 to 5% normal transcript in patient fibroblasts, consistent with a loss of function. The unaffected parents and an unaffected sib were heterozygous for the mutation, leading Rajab et al. (2015) to conclude that haploinsufficiency for DEAF1 does not cause symptoms.