Genotype-phenotype implications from three representative clinical FOXG1 variants associated with FOXG1 syndrome

Rare diseases affect an estimated 300 million individuals worldwide, and ∼30 million Americans. One of these diseases, FOXG1 syndrome, is a severe neurological condition that causes medical complications and developmental delays. The majority of those diagnosed with the genetic condition are children, making parenting a challenging experience. The purpose of this investigation was to explore the relationship between anxiety, coping, and stress among parents of children with FOXG1 syndrome, ( N = 84). The objective was to identify how these constructs relate and contribute to one another to best treat parents who are seeking counseling services. Results indicated significant relationships between these constructs. Study implications, limitations, and areas for future research are discussed.

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Human neuropathology confirms projection neuron and interneuron defects and delayed oligodendrocyte production and maturation in FOXG1 syndrome

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2021.104282 ◽

2021 ◽

pp. 104282

Author(s):

Nina-Maria Wilpert ◽

Florent Marguet ◽

Camille Maillard ◽

Fabien Guimiot ◽

Jelena Martinovic ◽

...

Keyword(s):

Projection Neuron ◽

Foxg1 Syndrome

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Loss of Foxg1 Impairs the Development of Cortical SST-Interneurons Leading to Abnormal Emotional and Social Behaviors

Cerebral Cortex ◽

10.1093/cercor/bhz114 ◽

2019 ◽

Vol 29 (8) ◽

pp. 3666-3682 ◽

Cited By ~ 2

Author(s):

Dongsheng Chen ◽

Chunlian Wang ◽

Meiyi Li ◽

Xinyu She ◽

Yonggui Yuan ◽

...

Keyword(s):

Intellectual Disability ◽

Social Interactions ◽

Social Communication ◽

Low Dose ◽

Emotional Disorder ◽

Membrane Excitability ◽

Cellular Basis ◽

Foxg1 Syndrome ◽

Cognitive Defects

Abstract FOXG1 syndrome is a severe encephalopathy that exhibit intellectual disability, emotional disorder, and limited social communication. To elucidate the contribution of somatostatin-expressing interneurons (SST-INs) to the cellular basis underlying FOXG1 syndrome, here, by crossing SST-cre with a Foxg1fl/fl line, we selectively ablated Foxg1. Loss of Foxg1 resulted in an obvious reduction in the number of SST-INs, accompanied by an altered ratio of subtypes. Foxg1-deficient SST-INs exhibited decreased membrane excitability and a changed ratio of electrophysiological firing patterns, which subsequently led to an excitatory/inhibitory imbalance. Moreover, cognitive defects, limited social interactions, and depression-like behaviors were detected in Foxg1 cKO mice. Treatment with low-dose of clonazepam effectively alleviated the defects. These results identify a link of SST-IN development to the aberrant emotion, cognition, and social capacities in patients. Our findings identify a novel role of Foxg1 in SST-IN development and put new insights into the cellular basis of FOXG1 syndrome.

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Foxg1 Regulates the Postnatal Development of Cortical Interneurons

Cerebral Cortex ◽

10.1093/cercor/bhy051 ◽

2018 ◽

Vol 29 (4) ◽

pp. 1547-1560 ◽

Cited By ~ 12

Author(s):

Wei Shen ◽

Ru Ba ◽

Yan Su ◽

Yang Ni ◽

Dongsheng Chen ◽

...

Keyword(s):

Postnatal Development ◽

Neural Circuit ◽

Neurological Diseases ◽

Cortical Interneuron ◽

Conditional Deletion ◽

Cortical Interneurons ◽

Migration Capacity ◽

Dendritic Complexity ◽

Foxg1 Syndrome

AbstractAbnormalities in cortical interneurons are closely associated with neurological diseases. Most patients with Foxg1 syndrome experience seizures, suggesting a possible role of Foxg1 in the cortical interneuron development. Here, by conditional deletion of Foxg1, which was achieved by crossing Foxg1fl/fl with the Gad2-CreER line, we found the postnatal distributions of somatostatin-, calretinin-, and neuropeptide Y-positive interneurons in the cortex were impaired. Further investigations revealed an enhanced dendritic complexity and decreased migration capacity of Foxg1-deficient interneurons, accompanied by remarkable downregulation of Dlx1 and CXCR4. Overexpression of Dlx1 or knock down its downstream Pak3 rescued the differentiation detects, demonstrated that Foxg1 functioned upstream of Dlx1-Pak3 signal pathway to regulate the postnatal development of cortical interneurons. Due to the imbalanced neural circuit, Foxg1 mutants showed increased seizure susceptibility. These findings will improve our understanding of the postnatal development of interneurons and help to elucidate the mechanisms underlying seizure in patients carrying Foxg1 mutations.

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A Forkhead box G1 (FOXG1) gene mutation in an Indian patient with a congenital variant of Rett syndrome.

Pediatric Review International Journal of Pediatric Research ◽

10.17511/ijpr.2020.i08.09 ◽

2020 ◽

Vol 7 (8) ◽

pp. 442-445

Author(s):

Dr. Sai Chandar Dudipala ◽

◽

Dr. Naveen Reddy Cheruku ◽

Dr. Krishna Chaithanya Battu ◽

◽

...

Keyword(s):

Rett Syndrome ◽

Frameshift Mutation ◽

Global Developmental Delay ◽

Separate Entity ◽

Indian Patient ◽

Forkhead Box ◽

History Of ◽

Foxg1 Syndrome ◽

Congenital Variant ◽

Atypical Variant

A congenital variant of rett syndrome or Forkhead box G1 (FOXG1) syndrome is a rareneurodevelopmental disorder characterized by global developmental delay, microcephaly, autisticfeatures, early-onset dyskinesia, and seizures. Once it was described as one atypical variant of rettsyndrome but now considered as a separate entity. The current study found one girl carrying the denovo c.500-501incG frameshift mutation in the FOXG1 gene by genetic analysis during theevaluation for severe chronic encephalopathy. In literature, only one case was reported from Indiawith FOXG1 mutation. The FOXG1 mutation should be considered in children with a history of globaldevelopmental delay, dyskinesia, and microcephaly with characteristic brain neuroimaging findings.

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