Loss-of-function mutation of collybistin is responsible for X-linked mental retardation associated with epilepsy.

Microarray-based comparative genomic hybridization analysis identified a 737-kb microdeletion of Xq11.1, including the cell division cycle 42 guanine nucleotide exchange factor (GEF)-9 gene (ARHGEF9), encoding collybistin, which has a pivotal role in formation of postsynaptic glycine and γ-aminobutyric acid receptor clusters, in a male patient with severe mental retardation and epilepsy. No overlapping deletion with this was identified in the database of genomic copy number variations. A cohort study of ARHGEF9 nucleotide sequence identified a nonsense mutation in another male patient with severe mental retardation and epilepsy. This mutation affects one of the three transcript variants of ARHGEF9, which was confirmed to be expressed in the brain by reverse transcription-PCR. Although this nonsense mutation was shared with the patient's mother, it was not observed in 100 normal individuals. Both male patients suffered epileptic seizures after 1 year of age. Brain magnetic resonance imaging revealed mild frontal atrophy in the first patient and right frontal polymicrogyria in the second patient. Three previously reported mutations of ARHGEF9 consisted of a missense mutation in a male patient with hyperekplexia and two chromosomal disruptions in two female patients. The common phenotypic effects of all ARHGEF9 mutations were mental retardation and epilepsy. Therefore, ARHGEF9 is likely to be responsible for syndromic X-linked mental retardation associated with epilepsy.