Revisiting the phenotype associated with FOXG1 mutations: two novel cases of congenital Rett variant
The Forkhead box G1 (FOXG1) is a transcription factor that is critical for forebrain development, where it promotes progenitor proliferation and suppresses premature neurogenesis. Recently, the FOXG1 gene was implicated in the molecular aetiology of the congenital variant of Rett syndrome. So far, 15 FOXG1 molecular alterations, including only eight point mutations, have been reported. 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. The screening was negative in all males, but two de novo mutations (c.1248C>G, p.Y416X and c.460_461dupG, p.E154GfsX300) were identified in two unrelated girls. Both patients showed neurological symptoms from the neonatal period with poor reactivity, hypotonia, and severe microcephaly. During the first year of life, both patients had feeding difficulties and made slow developmental progress. At 5 years old, the girls were significantly neurologically impaired with gross hypotonia, no language, convergent strabismus, and no voluntary hand use. Moreover, they presented a combination of jerky movements, hand-mouthing, and hand-washing stereotypies. Hence, FOXG1 mutation patients demonstrate severe encephalopathy compatible with the congenital variant, as well as additional features such as absent eye contact, inconsolable crying during the perinatal period, and delayed myelination with thin to hypoplastic corpus callosum. Although the overall frequency of mutations in FOXG1 in females with severe mental retardation and microcephaly appears to be low (1.5%), our findings suggest the requirement to investigate both point mutations and gene dosage in the FOXG1 gene in patients with severe encephalopathy with microcephaly and some Rett-like features.
KeywordsRett syndrome Congenital variant Encephalopathy FOXG1
We thank the patients, clinicians, and families who helped the study. This work was supported by the Institut National de la Santé et de la Recherche Médicale (ANR e-RARE EURORett).
Video electroencephalogram showing abnormal dyskinetic and non-epileptic movement disorder. (WMV 1857 kb)
- 9.Jacob FD, Ramaswamy V, Andersen J, Bolduc FV (2009) Atypical Rett syndrome with selective FOXG1 deletion detected by comparative genomic hybridization: case report and review of literature. Eur J Hum Genet (in press)Google Scholar
- 10.Mencarelli M, Spanhol-Rosseto A, Artuso R et al (2009) Novel FOXG1 mutations associated with the congenital variant of Rett syndrome. J Med Genet (in press)Google Scholar
- 11.Philippe C, Amsallem D, Francannet C et al (2009) Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females. J Med Genet (in press)Google Scholar