Cortical Dysplasia, Complex, With Other Brain Malformations 3

A number sign (#) is used with this entry because of evidence that complex cortical dysplasia with other brain malformations-3 (CDCBM3) is caused by heterozygous mutation in the KIF2A gene (602591) on chromosome 5q12.

For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039).

Clinical Features

Poirier et al. (2013) reported 2 unrelated children with microcephaly (-4 SD and -2.5 SD, respectively), early-onset epilepsy, and various malformations of cortical development, including agyria, posterior or frontal pachygyria, subcortical band heterotopia, and thin corpus callosum. One patient had dysmorphic basal ganglia. Brainstem and cerebellum were normal in both patients. Both had severe developmental delay and were bedridden with spastic paraplegia at ages 1 and 4 years, respectively.

Molecular Genetics

In 2 unrelated patients with complex cortical dysplasia and microcephaly, Poirier et al. (2013) identified different de novo heterozygous mutations in the KIF2A gene (H321D, 602591.0001 and S317N, 602591.0002). The first mutation was found by whole-exome sequencing and was not present in several genomic databases, including dbSNP, 1000 Genomes, the Exome Variant Server, and a local Paris Descartes Bioinformatics platform database. The second mutation was found by screening 162 individuals with various malformations of cortical development for variants in kinesin genes. In vitro functional expression studies showed that both mutations caused abnormal protein folding, resulting in abnormal cellular localization and a loss of protein function. Because KIF2A functions as a dimer, Poirier et al. (2013) postulated a dominant-negative effect. The findings extended the association between microtubule-based cellular processes and proper cortical development.