Homozygous knockout of Foxg1 in mice leads to severe microcephaly, attributed to premature differentiation of telencephalic progenitors, mainly of cortical progenitors.
More recently, point mutations in DYRK1A have been shown to be responsible for a recognizable syndrome characterized by microcephaly, developmental delay and intellectual disability (ID) as well as characteristic facial features.
Its complete absence is embryonic lethal while Foxg1 heterozygous mice are viable but display microcephaly, altered hippocampal neurogenesis and behavioral and cognitive deficiencies.
Microcephaly 2 (MCPH2) is one of the most frequent subtypes of MCPH.WD repeat-containing protein 62 gene (WDR62) is the most frequently mutated gene in MCPH2 patients.
In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain.
FOXG1-related disorders are caused by heterozygous mutations in FOXG1 and result in a spectrum of neurodevelopmental phenotypes including postnatal microcephaly, intellectual disability with absent speech, epilepsy, chorea, and corpus callosum abnormalities.
Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females.
Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD.
Children with deletions or intragenic mutations of FOXG1 also have postnatal microcephaly, morphologic abnormalities of the corpus callosum, and choreiform movements.
Human DYRK1A lies in the Down syndrome critical region on chromosome 21, and heterozygous mutations in the gene cause microcephaly and neurological dysfunction.
Hypo- or agenesis of the anterior corpus callosum in combination with acquired microcephaly and neurologic impairment can be an important clue for identifying patients with a mutation in FOXG1.
Thus, we hypothesize that FOXG1 might be a new candidate gene in the etiology of LGS and suggest screening for this gene in cases of LGS with concomitant microcephaly and clinical features overlapping with Rett syndrome.
We propose that a disruption of centrosome integrity and/or spindle organization may play an important role in the development of microcephaly in MCPH2.
We believe that the FOXG1 gene should be considered in severely mentally retarded patients (no speech-language) with severe acquired microcephaly (-4 to-6 SD) and few clinical features suggestive of Rett syndrome.
WD40-repeat protein 62 (WDR62) was recently identified as a spindle pole protein linked to the neurodevelopmental defect of microcephaly but its roles in mitosis have not been defined.
Our data support associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a β-catenin-chromatin-remodeling network to ASD etiology.
The DYRK1A gene was studied by direct sequencing and quantitative PCR in a cohort of 105 patients with ID and at least two symptoms from the Angelman syndrome spectrum (microcephaly < -2.5 SD, ataxic gait, seizures and speech delay).
Recently, CASK aberrations caused by both mutations and deletions have been reported to cause severe mental retardation (MR), microcephaly and disproportionate pontine and cerebellar hypoplasia (MICPCH) in females.
Heterozygous loss of function mutations of CASK at Xp11.4 in females cause severe intellectual disability (ID) and microcephaly with pontine and cerebellar hypoplasia (MICPCH).
CASK mutations have been reported in patients with intellectual disability with microcephaly and pontocerebellar hypoplasia or congenital nystagmus, and those with FG syndrome.
We screened the FOXG1 gene in a cohort of 206 MECP2 and CDKL5 mutation negative patients (136 females and 70 males) with severe encephalopathy and microcephaly.