A FOXG1 mutation in a boy with congenital variant of Rett syndrome

Guen, Tangui Le; Bahi‐Buisson, Nadia; Nectoux, Juliette; Boddaert, Nathalie; Fichou, Yann; Diebold, Bertrand; Desguerre, Isabelle; Raqbi, F; Cormier‐Daire, Valérie; Chelly, Jamel; Bienvenu, Thierry

doi:10.1007/s10048-010-0255-4

Cited by 40 publications

(51 citation statements)

References 20 publications

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“…[5][6]17 The same c.256dupC frameshift has already been reported twice in patients with congenital RTT. 7,18 The c.256del/dup is the second mutational hot spot affecting a mononucleotide repeat in FOXG1. We also describe five new CNVs in 14q12 in two males and three females.…”

Section: Discussionmentioning

confidence: 99%

“…Point mutations in the Forkhead box G1 (FOXG1) gene, encoding a brain-specific transcriptional repressor essential for the development of the telencephalon, were found to be responsible for congenital [1][2][3][4][5][6][7] or classical 2,5 Rett syndrome (RTT) in females and also in males. [5][6][7] Copy number variations (CNV) in 14q12 containing the FOXG1 gene have been identified in both genders in patients suffering from neurodevelopmental disorders.…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7] Copy number variations (CNV) in 14q12 containing the FOXG1 gene have been identified in both genders in patients suffering from neurodevelopmental disorders. Microdeletions in 14q12 were described in patients with early-onset Rett-like phenotypes associated with facial dysmorphic features.…”

Section: Introductionmentioning

confidence: 99%

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14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements

et al. 2012

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The Forkhead box G1 (FOXG1) gene has been implicated in severe Rett-like phenotypes. It encodes the Forkhead box protein G1, a winged-helix transcriptional repressor critical for forebrain development. Recently, the core FOXG1 syndrome was defined as postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and dysgenesis of the corpus callosum. We present seven additional patients with a severe Rett-like neurodevelopment disorder associated with de novo FOXG1 point mutations (two cases) or 14q12 deletions (five cases). We expand the mutational spectrum in patients with FOXG1-related encephalopathies and precise the core FOXG1 syndrome phenotype. Dysgenesis of the corpus callosum and dyskinesia are not always present in FOXG1-mutated patients. We believe that the FOXG1 gene should be considered in severely mentally retarded patients (no speech-language) with severe acquired microcephaly ( À4 to À6 SD) and few clinical features suggestive of Rett syndrome. Interestingly enough, three 14q12 deletions that do not include the FOXG1 gene are associated with phenotypes very reminiscent to that of FOXG1-mutation-positive patients. We physically mapped a putative long-range FOXG1-regulatory element in a 0.43 Mb DNA segment encompassing the PRKD1 locus. In fibroblast cells, a cis-acting regulatory sequence located more than 0.6 Mb away from FOXG1 acts as a silencer at the transcriptional level. These data are important for clinicians and for molecular biologists involved in the management of patients with severe encephalopathies compatible with a FOXG1-related phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements

et al. 2012

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“…The mutation has been previously identified in both a female and a male with congenital variant of Rett syndrome. 24,26 Screening of the same 32 patients did not reveal any pathogenic mutations in PRKD1, a protein kinase involved in extracellular receptor-mediated signal transduction pathways. A number of known nonpathogenic polymorphisms were identified and shown in Table 2.…”

Section: Chromosomal Microarray Analysismentioning

confidence: 93%

“…17 Philippe et al, 25 Le Guen et al, 24,35 Mencarelli et al, 15 Bahi-Buisson et al, 16 Takahashi et al 26 …”

Section: Chromosomal Microarray Analysis Methodsunclassified

14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype

Ellaway

Bettella

et al. 2012

Eur J Hum Genet

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Rett syndrome is a clinically defined neurodevelopmental disorder almost exclusively affecting females. Usually sporadic, Rett syndrome is caused by mutations in the X-linked MECP2 gene in B90-95% of classic cases and 40-60% of individuals with atypical Rett syndrome. Mutations in the CDKL5 gene have been associated with the early-onset seizure variant of Rett syndrome and mutations in FOXG1 have been associated with the congenital Rett syndrome variant. We report the clinical features and array CGH findings of three atypical Rett syndrome patients who had severe intellectual impairment, early-onset developmental delay, postnatal microcephaly and hypotonia. In addition, the females had a seizure disorder, agenesis of the corpus callosum and subtle dysmorphism. All three were found to have an interstitial deletion of 14q12. The deleted region in common included the PRKD1 gene but not the FOXG1 gene. Gene expression analysis suggested a decrease in FOXG1 levels in two of the patients. Screening of 32 atypical Rett syndrome patients did not identify any pathogenic mutations in the PRKD1 gene, although a previously reported frameshift mutation affecting FOXG1 (c.256dupC, p.Gln86ProfsX35) was identified in a patient with the congenital Rett syndrome variant. There is phenotypic overlap between congenital Rett syndrome variants with FOXG1 mutations and the clinical presentation of our three patients with this 14q12 microdeletion, not encompassing the FOXG1 gene. We propose that the primary defect in these patients is misregulation of the FOXG1 gene rather than a primary abnormality of PRKD1.

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Familial recurrences of FOXG1‐related disorder: Evidence for mosaicism

McMahon

Papandreou

et al. 2015

American J of Med Genetics Pt A

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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. The recurrence risk for de novo mutations in FOXG1-related disorders is assumed to be low. Here, we describe three unrelated sets of full siblings with mutations in FOXG1 (c.515_577del63, c.460dupG, and c.572T>G), representing familial recurrence of the disorder. In one family, we have documented maternal somatic mosaicism for the FOXG1 mutation, and all of the families presumably represent parental gonadal (or germline) mosaicism. To our knowledge, mosaicism has not been previously reported in FOXG1-related disorders. Therefore, this report provides evidence that germline mosaicism for FOXG1 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling for families of children with FOXG1-related disorders.

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A FOXG1 mutation in a boy with congenital variant of Rett syndrome

Cited by 40 publications

References 20 publications

14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements

14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements

14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype

Familial recurrences of FOXG1‐related disorder: Evidence for mosaicism

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