West syndrome associated with 14q12 duplications harboring FOXG1

Striano, Pasquale; Paravidino, Roberta; Sicca, Federico; Chiurazzi, Pietro; Gimelli, Stefania; Robbiano, Angela; Traverso, Monica; Pintaudi, Maria; Giovannini, S.; Operto, Francesca Felicia; Vigliano, Piernanda; Granata, Tiziana; Coppola, Giangennaro; Romeo, Antonino; Specchio, Nicola; Giordano, Lucio; Osborne, LR; Gimelli, Giorgio; Minetti, Carlo; Zara, Federico

doi:10.1212/wnl.0b013e3182194bbf

Cited by 51 publications

(42 citation statements)

References 6 publications

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“…In contrast to phenotypically well-defined genomic duplications of MECP2 in males (OMIM 300260) and of FOXG1, [25][26][27][28][29][30] the clinical consequences of increased dosage of CDKL5 are poorly understood. Thus far, only larger-sized (8-21 Mb) Xp22 duplications involving CDKL5 have been described, [31][32][33][34] making phenotypic contribution of CDKL5 duplication challenging to dissect.…”

Section: Introductionmentioning

confidence: 98%

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

Szafrański

Golla²,

Jin

et al. 2014

Eur J Hum Genet

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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.

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Section: Introductionmentioning

confidence: 98%

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

Szafrański

Golla²,

Jin

et al. 2014

Eur J Hum Genet

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“…7,8,[12][13][14] Mutation analyses have identified de novo loss-of-function point mutations in FOXG1, particularly in patients with the congenital form of Rett syndrome. [15][16][17] Duplications of FOXG1 are also found in patients with epilepsy and intellectual impairment, [18][19][20][21] highlighting the importance of gene dosage at this locus, although more recently the pathogenicity of FOXG1 duplications has been questioned. 22 We report the clinical features and array CGH findings of three atypical Rett syndrome patients.…”

Section: Introductionmentioning

confidence: 99%

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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“…Previously, we had reported a similarly affected patient with a deletion that also included FOXG1, 2 and more recently three patients with West syndrome were reported to have duplications that included FOXG1. 3,4 FOXG1 encodes a brainspecific transcriptional repressor, 5 and deletions and point mutations in FOXG1 are known to cause the congenital variant of Rett syndrome, 6 making duplication of FOXG1 a strong candidate for the neurocognitive impairment in patient with 14q12 duplications.…”

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confidence: 99%

“…1-2 Such association has been confirmed subsequently in other patients. [3][4] However, Amor et al 5 have found an B88 kb duplication at 14q12, encompassing the FOXG1 and C14orf23 genes in a father-son pair with isolated hemifacial microsomia. Neither the son nor the father exhibited mental retardation or epilepsy.…”

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confidence: 99%