Dysregulation of FOXG1 by ring chromosome 14

Alosi, Daniela; Klitten, Laura L.; Bak, Mads; Hjalgrim, Helle; Møller, Rikke S.; Tommerup, Niels

doi:10.1186/s13039-015-0129-4

Cited by 9 publications

(9 citation statements)

References 23 publications

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“…Due to long-range position effects (LRPE), chromosomal breakpoints 3 to FOXG1 lead to a congenital variant of Rett syndrome, similar to FOXG1 intragenic point mutations (Fig. 1) [5][6][7]. Intergenic deletions have defined an ~430 kb (chr14:29,875,672- [5-7, 16, 23] and red bars indicate patients in the present study (P1-P6).…”

Section: Introductionmentioning

confidence: 90%

Regulatory variants of FOXG1 in the context of its topological domain organisation

et al. 2017

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FOXG1 syndrome is caused by FOXG1 intragenic point mutations, or by long-range position effects (LRPE) of intergenic structural variants. However, the size of the FOXG1 regulatory landscape is uncertain, because the associated topologically associating domain (TAD) in fibroblasts is split into two domains in embryonic stem cells (hESC). Indeed, it has been suggested that the pathogenetic mechanism of deletions that remove the stem-cell-specific TAD boundary may be enhancer adoption due to ectopic activity of enhancer(s) located in the distal hESC-TAD. Herein we map three de novo translocation breakpoints to the proximal regulatory domain of FOXG1. The classical FOXG1 syndrome in these and in other translocation patients, and in a patient with an intergenic deletion that removes the hESC-specific TAD boundary, do not support the hypothesised enhancer adoption as a main contributor to the FOXG1 syndrome. Also, virtual 4 C and HiC-interaction data suggest that the hESC-specific TAD boundary may not be critical for FOXG1 regulation in a majority of human cells and tissues, including brain tissues and a neuronal progenitor cell line. Our data support the importance of a critical regulatory region (SRO) proximal to the hESC-specific TAD boundary. We further narrow this critical region by a deletion distal to the hESC-specific boundary, associated with a milder clinical phenotype. The distance from FOXG1 to the SRO ( > 500 kb) highlight a limitation of ENCODE DNase hypersensitivity data for functional prediction of LRPE. Moreover, the SRO has little overlap with a cluster of frequently associating regions (FIREs) located in the proximal hESC-TAD.

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Section: Introductionmentioning

confidence: 90%

Regulatory variants of FOXG1 in the context of its topological domain organisation

et al. 2017

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“…It was speculated that the formation of the ring could induce the spreading of heterochromatinization and dysregulate the gene expression [ 26 ]. Dysregulation of FOXG1 gene by an acentric ring chromosome 14 was noted in a patient with epilepsy [ 27 ]. Based on the clinical types per cytogenomic findings and reproductive patterns from male and female carriers per family history, recommendations for cytogenomic analysis specific for ring chromosome 21 was proposed [ 4 ].…”

Section: Toward Precise Genetic Diagnosis and Clinical Managementmentioning

confidence: 99%

Human ring chromosome registry for cases in the Chinese population: re-emphasizing Cytogenomic and clinical heterogeneity and reviewing diagnostic and treatment strategies

Chai²,

Shu

et al. 2018

Mol Cytogenet

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BackgroundConstitutional ring chromosomes are rare orphan chromosomal disorders. Ring chromosome syndrome featuring growth retardation and mild to intermediate intellectual disability is likely caused by the dynamic behavior of ring chromosome through cell cycles. Chromosomal and regional specific phenotypes likely result from segmental losses and gains during the ring formation. Although recent applications of genomic copy number and sequencing analyses revealed various ring chromosome structures from an increasing number of case studies, there was no organized effort for compilating and curating cytogenomic and clinical finding for ring chromosomes.MethodsA web-based interactive ‘Human Ring Chromosome Registry’ using Microsoft Access based relational database was developed to present genetic and phenotypic findings of ring chromosome cases. Chinese ring chromosome cases reported in the literature was reviewed and compiled as a testing data set to validate this registry.ResultsA total of 113 cases of ring chromosomes were retrieved in all chromosomes except for chromosomes 16, 17 and 19. The most frequently seen ring chromosomes by a decreasing order of relative frequencies were ring 13 (14%), X (12%), 22 (10%), 15 (9%), 14 (7%), and 18 (7%). Genomic imbalances were detected in 18 out of 19 cases analyzed by microarray or sequencing. Variable clinical manifestations of developmental delay, dysmorphic facial features, intellectual disability, microcephaly, and hypotonia were noted in most autosomal rings. Chromosomal specific syndromic phenotypes included Wolf-Hirschhorn syndrome in a ring chromosome 4, cri-du-chat syndrome in a ring chromosome 5, epilepsy in ring chromosomes 14 and 20, Turner syndrome in ring chromosome X, and infertility in ring chromosomes 13, 21, 22 and Y. Effective growth hormone supplemental treatment for growth retardation in a ring chromosome 18 was noted.ConclusionsBased on findings from these Chinese ring chromosome cases, guidelines for cytogenomic diagnosis and criteria for case registration were proposed. Further research to define underlying mechanisms of ring chromosome formation and dynamic mosaicism, to delineate the genotype-phenotype correlations, and to develop chromosome therapy for ring chromosomes were discussed.Electronic supplementary materialThe online version of this article (10.1186/s13039-018-0367-3) contains supplementary material, which is available to authorized users.

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“…Chromosomal structural variants resulting in a "congenital variant of Rett syndrome" have been previously described, as well as cases of deletions resulting in the disruption of FOXG1 regulatory elements [19][20][21]. Other reports have found examples of chromosomal structural variants disrupting FOXG1 regulatory elements [8,13,[22][23][24]. Mehrjouy et al published one of the more comprehensive investigations into regulatory variants in FOXG1 syndrome, examining the role of topologically associated domains and long range positional effects on FOXG1 expression [11].…”

Section: Discussionmentioning

confidence: 99%

Diagnosis of FOXG1 syndrome caused by recurrent balanced chromosomal rearrangements: case study and literature review

et al. 2020

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Background: The FOXG1 gene plays a vital role in mammalian brain differentiation and development. Intra-and intergenic mutations resulting in loss of function or altered expression of the FOXG1 gene cause FOXG1 syndrome. The hallmarks of this syndrome are severe developmental delay with absent verbal language, post-natal growth restriction, post-natal microcephaly, and a recognizable movement disorder characterized by chorea and dystonia. Case presentation: Here we describe a case of a 7-year-old male patient found to have a de novo balanced translocation between chromosome 3 at band 3q14.1 and chromosome 14 at band 14q12 via G-banding chromosome and Fluorescence In Situ Hybridization (FISH) analyses. This rearrangement disrupts the proximity of FOXG1 to a previously described smallest region of deletion overlap (SRO), likely resulting in haploinsufficiency. Conclusions: This case adds to the growing body of literature implicating chromosomal structural variants in the manifestation of this disorder and highlights the vital role of cis-acting regulatory elements in the normal expression of this gene. Finally, we propose a protocol for reflex FISH analysis to improve diagnostic efficiency for patients with suspected FOXG1 syndrome.

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Dysregulation of FOXG1 by ring chromosome 14

Cited by 9 publications

References 23 publications

Regulatory variants of FOXG1 in the context of its topological domain organisation

Regulatory variants of FOXG1 in the context of its topological domain organisation

Human ring chromosome registry for cases in the Chinese population: re-emphasizing Cytogenomic and clinical heterogeneity and reviewing diagnostic and treatment strategies

Diagnosis of FOXG1 syndrome caused by recurrent balanced chromosomal rearrangements: case study and literature review

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