Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females

Philippe, Christophe; Amsallem, D.; Francannet, Christine; Lambert, Laëtitia; Saunier, Aline; Verneau, F.; Jonveaux, Philippe

doi:10.1136/jmg.2009.067355

Cited by 83 publications

(87 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…25 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. The commonly deleted region is B260 kb and includes the PRKD1 gene but not the FOXG1 gene.…”

Section: Discussionmentioning

confidence: 65%

See 1 more Smart Citation

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

Ellaway

Bettella

et al. 2012

Eur J Hum Genet

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 65%

“…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

View full text Add to dashboard Cite

show abstract

“…Point mutations or genomic deletions in MECP2 have been identified in greater than 90% of patients with typical Rett syndrome. 1,2 In 30-50% of patients with atypical Rett syndrome, 3 negative for alterations in MECP2, intragenic changes in CDKL5 [4][5][6][7][8] or in FOXG1 [9][10][11] have been reported.…”

Section: Introductionmentioning

confidence: 99%

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

Szafrański

Golla²,

Jin

et al. 2014

Eur J Hum Genet

View full text Add to dashboard Cite

Point mutations and genomic deletions of the CDKL5 (STK9) gene on chromosome Xp22 have been reported in patients with severe neurodevelopmental abnormalities, including Rett-like disorders. To date, only larger-sized (8-21 Mb) duplications harboring CDKL5 have been described. We report seven females and four males from seven unrelated families with CDKL5 duplications 540-935 kb in size. Three families of different ethnicities had identical 667 kb duplications containing only the shorter CDKL5 isoform. Four affected boys, 8-14 years of age, and three affected girls, 6-8 years of age, manifested autistic behavior, developmental delay, language impairment, and hyperactivity. Of note, two boys and one girl had macrocephaly. Two carrier mothers of the affected boys reported a history of problems with learning and mathematics while at school. None of the patients had epilepsy. Similarly to CDKL5 mutations and deletions, the X-inactivation pattern in all six studied females was random. We hypothesize that the increased dosage of CDKL5 might have affected interactions of this kinase with its substrates, leading to perturbation of synaptic plasticity and learning, and resulting in autistic behavior, developmental and speech delay, hyperactivity, and macrocephaly.

show abstract

“…In a recent series of articles, several groups identified ten different mutations in FOXG1 as the cause of the congenital form of Rett syndrome (RTT; MIM# 312750) [Ariani et al, 2008;Philippe et al, 2010;Mencarelli et al, 2010;Bahi-Buisson et al, 2010]. All patients fulfilled the criteria of the congenital variant of RTT except one presenting a classical form of Rett syndrome [Philippe et al, 2010].…”

Section: Introductionmentioning

confidence: 99%

“…All patients fulfilled the criteria of the congenital variant of RTT except one presenting a classical form of Rett syndrome [Philippe et al, 2010]. The congenital variant of RTT, which was initially described by Rolando in 1985[Rolando et al, 1985, involves girls that present with a normal perinatal period followed by a phase of developmental regression at the age of 3-6 months.…”

Section: Introductionmentioning

confidence: 99%

A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization

et al. 2010

View full text Add to dashboard Cite

ABSTRACT:The forkhead box G1 (FOXG1) gene has recently been associated with the congenital variant of Rett syndrome, and so far 17 mutations have been reported. We screened the coding region in 150 patients affected by postnatal microcephaly, and identified two mutations: the c.326C>T (p.P109L) substitution inherited from the healthy father; and the de novo c.730C>T transition, which induces the p.R244C mutation within the DNA-binding forkhead domain. This latter mutation is carried by an 8-year-old girl, who presented a phenotype reminiscent of the congenital variant of Rett syndrome. Immunofluorescence analysis of the wild-type protein revealed a homogeneous nuclear staining excluding the nucleoli, while the p.R244C mutant showed abnormal nuclear foci in a large proportion of cells, suggesting that its mislocalization may reduce and/or impair target recognition. Interestingly, this missense mutation results in a mislocalization of FoxG1 to specific nuclear foci referred to as nuclear speckles, and affects the cyclin-dependent kinase inhibitor p21 CDKN1A expression. Because CDKL5, which is involved in the early-onset variant of Rett syndrome, is also located in these speckles, we suggest that disregulation of the dynamic behaviour of nuclear speckles may functionally link these two proteins, which are both involved in atypical forms of Rett syndrome.

show abstract

Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females

Abstract: These new cases give additional support to the genetic heterogeneity in RTT and help to delineate the clinical spectrum of the FOXG1-related phenotypes. FOXG1 screening should be considered in the molecular diagnosis of RTT.

Cited by 83 publications

References 29 publications

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

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

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization

Contact Info

Product

Resources

About