Further delineation of the phenotype of chromosome 14q13 deletions: (positional) involvement of<i>FOXG1</i>appears the main determinant of phenotype severity, with no evidence for a holoprosencephaly locus

Santen, Gijs; Sun, Yu; Gijsbers, Antoinet C.J.; Carré, Aurore; Holvoet, Maureen; Haeringen, Arie van; Oberstein, Saskia A J Lesnik; Tomoda, Akemi; Mabe, Hiroyo; Polak, Michel; Devriendt, Koenraad; Ruivenkamp, Claudia; Bijlsma, Emilia K.

doi:10.1136/jmedgenet-2011-100721

Cited by 26 publications

(36 citation statements)

References 29 publications

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“…This finding, together with 14q12 deletions that do not harbor the FOXG1 gene but associated with a similar phenotype to that of FOXG1 mutation-positive patients, strongly suggests the presence of long-range regulatory elements of FOXG1. 14,16,[18][19][20] Our study further supports the existence of a long-range regulatory region. The three 14q12 translocations in this study are associated with a lower FOXG1 expression and have their breakpoint at a distance of 200 kb up to 55 6kb downstream of FOXG1 gene.…”

Section: Discussionsupporting

confidence: 80%

“…16 This finding, together with a similar Rett syndrome-like phenotype in patients with 14q12 deletions that do not harbor the FOXG1 gene, strongly suggests the presence of long-range regulatory elements for FOXG1 expression in this region. 16,[18][19][20] We here report three de novo chromosome 14q12 translocations and one microdeletion in the 14q12 region in unrelated patients with microcephaly, severe intellectual disability, absent language, seizures, and corpus callosum hypoplasia. FOXG1 is a transcriptional repressor believed to be restricted to fetal and adult brain and testis.…”

Section: Introductionmentioning

confidence: 81%

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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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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 81%

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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“…Together, the alobar HPE phenotypes of Six3 neo/-embryos are most likely caused by the combination of Foxg1 downregulation in the anterior neural plate and Shh reduction in the RDVM. Therefore, mutations in Foxg1 alone are unlikely to result in HPE (Santen et al, 2012). Screening additional FOXG1 mutations in cases of familial HPE might shed additional light on the pathological variability of HPE.…”

Section: Six3 Dosage During Mammalian Forebrain Developmentmentioning

confidence: 99%

Six3 dosage mediates the pathogenesis of holoprosencephaly

et al. 2016

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Holoprosencephaly (HPE) is defined as the incomplete separation of the two cerebral hemispheres. The pathology of HPE is variable and, based on the severity of the defect, HPE is divided into alobar, semilobar, and lobar. Using a novel hypomorphic Six3 allele, we demonstrate in mice that variability in Six3 dosage results in different HPE phenotypes. Furthermore, we show that whereas the semilobar phenotype results from severe downregulation of Shh expression in the rostral diencephalon ventral midline, the alobar phenotype is caused by downregulation of Foxg1 expression in the anterior neural ectoderm. Consistent with these results, in vivo activation of the Shh signaling pathway rescued the semilobar phenotype but not the alobar phenotype. Our findings show that variations in Six3 dosage result in different forms of HPE.

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“…Of these 60 patients, three had deletions also including other genes, and 57 had mutations restricted to ARID1B. Although it is well known that in some cases multiple genes in a microdeletion can cause part of the phenotype [Santen et al, 2012c], we have chosen to include the patients with an ARID1B deletion in the comparison because of their prior CSS diagnosis. For about 50% of those the clinical information has been updated by the referring clinicians.…”

Section: Phenotype Of Css Patients With Arid1b Mutationsmentioning

confidence: 99%

The ARID1B phenotype: What we have learned so far

Santen

Clayton‐Smith²

2014

American J of Med Genetics Pt C

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Evidence is now accumulating from a number of sequencing studies that ARID1B not only appears to be one of the most frequently mutated intellectual disability (ID) genes, but that the range of phenotypes caused by ARID1B mutations seems to be extremely wide. Thus, it is one of the most interesting ID genes identified so far in the exome sequencing era. In this article, we review the literature surrounding ARID1B and attempt to delineate the ARID1B phenotype. The vast majority of published ARID1B patients have been ascertained through studies of Coffin-Siris syndrome (CSS), which leads to bias when documenting the frequencies of phenotypic features. Additional observations of those individuals ascertained through exome sequencing studies helps in delineation of the broader clinical phenotype. We are currently establishing an ARID1B consortium, aimed at collecting ARID1B patients identified through genome-wide sequencing strategies. We hope that this endeavor will eventually lead to a more comprehensive view of the ARID1B phenotype.

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Further delineation of the phenotype of chromosome 14q13 deletions: (positional) involvement ofFOXG1appears the main determinant of phenotype severity, with no evidence for a holoprosencephaly locus

Abstract: FOXG1 appears the main determinant of the severity of phenotypes resulting from deletions including 14q13. The collected data show no evidence for a locus for holoprosencephaly in the 14q13 region, but a locus for agenesis of the corpus callosum cannot be excluded.

Cited by 26 publications

References 29 publications

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

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

Six3 dosage mediates the pathogenesis of holoprosencephaly

The ARID1B phenotype: What we have learned so far

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