Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment

Brunetti‐Pierri, Nicola; Paciorkowski, Alex R.; Ciccone, Roberto; Mina, Erika Della; Bonaglia, María Clara; Borgatti, Renato; Schaaf, Christian P.; Sutton, V. Reid; Xia, Zhilian; Jelluma, Naftha; Ruivenkamp, Claudia; Bertrand, Mary; Ravel, Thomy de; Jayakar, Parul; Belli, Serena; Rocchetti, Katia; Pantaleoni, Chiara; D’Arrigo, Stefano; Hughes, J.B.; Cheung, Sau Wai; Zuffardi, Orsetta; Stankiewicz, Paweł

doi:10.1038/ejhg.2010.142

Cited by 110 publications

(128 citation statements)

References 27 publications

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“…8 This duplication is similar in size to the B3 Mb minimal duplicated region that includes FOXG1, c14orf32 and PRKD1 described in affected patients reported by Brunetti-Pierri et al 1 Patients carrying these small-sized duplications (cases 1 and 5 in Figure 1) were assessed as non-dysmorphic, so it is possible the healthy CHOP patient is yet to present with developmental problems, infantile spasms or other seizures. Alternatively, this case provides further evidence that FOXG1 duplication may be benign or incompletely penetrant.…”

supporting

confidence: 52%

“…1 Thus, it is not surprising that subjects at the mildest end of the spectrum may present with few or no clinically evident manifestations of the disease.…”

Section: Reply To Amor Et Almentioning

confidence: 99%

“…Recently in this journal, Brunetti-Pierri et al 1 published a report of seven patients with duplications at 14q12 that included the FOXG1 (MIM 164874). These patients presented with relatively severe neurodevelopmental phenotypes comprising intellectual disability, epilepsy and severe speech delay.…”

mentioning

confidence: 99%

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Questionable pathogenicity of FOXG1 duplication

et al. 2012

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supporting

confidence: 52%

“…1 Thus, it is not surprising that subjects at the mildest end of the spectrum may present with few or no clinically evident manifestations of the disease.…”

Section: Reply To Amor Et Almentioning

confidence: 99%

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Questionable pathogenicity of FOXG1 duplication

et al. 2012

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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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“…The importance of FOXG1 dosage during brain development is further suggested by the association of chromosome 14q12 duplications harboring FOXG1 with epilepsy, mental retardation, and severe speech impairment. [36][37][38][39] However, Amor et al 40 recently questioned the pathogenicity of FOXG1 duplications. Kortum et al 16 described one patient with mental retardation and postnatal microcephaly who carries a 2;14 translocation with the 14q12 breakpoint mapping in a region B265 kb downstream of FOXG1.…”

Section: Discussionmentioning

confidence: 99%

Platelet defects in congenital variant of Rett syndrome patients with FOXG1 mutations or reduced expression due to a position effect at 14q12

Goubau

Devriendt

et al. 2013

Eur J Hum Genet

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The Forkhead box G1 (FOXG1) gene encodes a transcriptional repressor essential for early development of the telencephalon. Intragenic mutations and gene deletions leading to haploinsufficiency cause the congenital variant of Rett syndrome. We here describe Rett syndrome-like patients, three of them carrying a balanced translocation with breakpoint in the chromosome 14q12 region, and one patient having a 14q12 microdeletion excluding the FOXG1 gene. The hypothesis of long-range FOXG1-regulatory elements in this region was supported by our finding of reduced FOXG1 mRNA and protein levels in platelets and skin fibroblasts from these cases. Given that FOXG1 is not only expressed in brain but also in platelets, we have studied platelet morphology in these patients and two additional patients with FOXG1 mutations. Electron microscopy of their platelets showed some enlarged, rounder platelets with often abnormal alpha, and fewer dense granules. Platelet function studies were possible in one 14q12 translocation patient with a prolonged Ivy bleeding time and a patient with a heterozygous FOXG1 c.1248C4G mutation (p.Tyr416X). Both have a prolonged PFA-100 occlusion time with collagen and epinephrine and reduced aggregation responses to low dose of ADP and epinephrine. Dense granule ATP secretion was normal for strong agonists but absent for epinephrine. In conclusion, our study shows that by using platelets functional evidence of cis-regulatory elements in the 14q12 region result in reduced FOXG1 levels in patients' platelets having translocations or deletions in that region. These platelet functional abnormalities deserve further investigation regarding a non-transcriptional regulatory role for FOXG1 in these anucleated cells.

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Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment

Cited by 110 publications

References 27 publications

Questionable pathogenicity of FOXG1 duplication

Questionable pathogenicity of FOXG1 duplication

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

Platelet defects in congenital variant of Rett syndrome patients with FOXG1 mutations or reduced expression due to a position effect at 14q12

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