FOXG1 – Rett syndrome

FOXG1 is a brain‐specific forkhead transcriptional repressor essential for early telencephalic development. Heterozygous loss-of-function variants in FOXG1 underlie the congenital variant of Rett syndrome, characterized by microcephaly, severe developmental delay, epilepsy, hypotonia and absent purposeful hand movements. Initial identification of truncating de novo FOXG1 mutations in two unrelated patients established its role in Rett syndrome ([PMID:18571142]).

Genetic evidence supports an autosomal dominant mode of inheritance with predominantly de novo heterozygous variants. In a cohort of 83 patients, 54 distinct FOXG1 variants—including 20 frameshifts, 17 missense alterations clustering in the forkhead domain, 15 nonsense alleles, and 2 in-frame changes—were identified in unrelated individuals, corroborating a strong gene–disease association ([PMID:28661489]).

Clinical reports describe over 60 unrelated probands harboring de novo FOXG1 variants, with no affected relatives, consistent with haploinsufficiency. Selected variants include c.385G>T (p.Glu129Ter) in a Chinese patient presenting with microcephaly, hypotonia, developmental regression and seizures ([PMID:36568277]). Phenotypic hallmarks encompass early postnatal microcephaly, developmental impairment, dyskinesia, corpus callosum hypogenesis and refractory epilepsy ([PMID:21441262]).

Functional studies demonstrate that FOXG1 haploinsufficiency disrupts neuronal differentiation and myelination. Conditional Foxg1 knockout in murine neural progenitors delays oligodendrocyte maturation and myelin formation during early postnatal brain development, with recovery by P30 ([PMID:37762220]). Visual cortical dysfunction in Foxg1(+/Cre) mice and human FOXG1-mutated individuals indicates high-level visual pathway impairment without retinal anomalies ([PMID:27001178]).

No studies to date have refuted the FOXG1–Rett syndrome association. Variants show consistent de novo occurrence, absence in controls, and concordant functional deficits across models. The convergence of genetic and experimental data over >15 years firmly establishes FOXG1 haploinsufficiency as a cause of congenital Rett syndrome.

Key Take-home: De novo heterozygous FOXG1 variants cause a definitive, autosomal dominant congenital Rett syndrome characterized by early microcephaly, severe neurodevelopmental impairment and epilepsy, with corroborating functional evidence from cellular and animal models, supporting diagnosis and potential therapeutic targeting.

References

• American Journal of Human Genetics | 2008 | FOXG1 is responsible for the congenital variant of Rett syndrome PMID:18571142
• Genetics in Medicine | 2018 | FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants PMID:28661489
• Journal of Medical Genetics | 2011 | The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis PMID:21441262
• International Journal of Molecular Sciences | 2023 | Conditional deletion of Foxg1 delayed myelination during early postnatal brain development PMID:37762220
• Neuroscience | 2016 | Visual impairment in FOXG1-mutated individuals and mice PMID:27001178
• Frontiers in Molecular Neuroscience | 2022 | Identification of a de novo mutation of the FOXG1 gene and comprehensive analysis for molecular factors in Chinese FOXG1-related encephalopathies PMID:36568277

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