CHD2 mutations are a rare cause of generalized epilepsy with myoclonic–atonic seizures

Trivisano, Marina; Striano, Pasquale; Sartorelli, Jacopo; Giordano, Lucio; Traverso, Monica; Accorsi, Patrizia; Cappelletti, Simona; Claps, Dianela; Vigevano, Federico; Zara, Federico; Specchio, Nicola

doi:10.1016/j.yebeh.2015.06.029

Cited by 34 publications

(35 citation statements)

References 18 publications

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“…Both girls developed seizures at age 3 year that is photosensitive and shared nearly identical manifestations including intellectual disability, abnormal EEG, and tonic-clonic seizure. Most patients carrying CHD2 mutation in literature developed seizure before 3 years of age2324252627, suggesting this gene might be critical for early brain development and function28. The nonsense mutation in our patients is located in the C terminus of CHD2 protein but it is not known whether the nonsense mediated decay mechanism is involved.…”

Section: Resultsmentioning

confidence: 77%

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Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing

Wang

Rao

et al. 2017

Sci Rep

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Genetic factors play a major role in the etiology of epilepsy disorders. Recent genomics studies using next generation sequencing (NGS) technique have identified a large number of genetic variants including copy number (CNV) and single nucleotide variant (SNV) in a small set of genes from individuals with epilepsy. These discoveries have contributed significantly to evaluate the etiology of epilepsy in clinic and lay the foundation to develop molecular specific treatment. However, the molecular basis for a majority of epilepsy patients remains elusive, and furthermore, most of these studies have been conducted in Caucasian children. Here we conducted a targeted exome-sequencing of 63 trios of Chinese epilepsy families using a custom-designed NGS panel that covers 412 known and candidate genes for epilepsy. We identified pathogenic and likely pathogenic variants in 15 of 63 (23.8%) families in known epilepsy genes including SCN1A, CDKL5, STXBP1, CHD2, SCN3A, SCN9A, TSC2, MBD5, POLG and EFHC1. More importantly, we identified likely pathologic variants in several novel candidate genes such as GABRE, MYH1, and CLCN6. Our results provide the evidence supporting the application of custom-designed NGS panel in clinic and indicate a conserved genetic susceptibility for epilepsy between Chinese and Caucasian children.

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Section: Resultsmentioning

confidence: 77%

“…The nonsense mutation in our patients is located in the C terminus of CHD2 protein but it is not known whether the nonsense mediated decay mechanism is involved. Two nearby frame-shift mutations (p.Arg1644Lysfs and p.Lys1419Argfs) have been reported in patients with myoclonic-astatic epilepsy2627. Both cases had early onset epileptic seizures.…”

Section: Resultsmentioning

confidence: 99%

Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing

Wang

Rao

et al. 2017

Sci Rep

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“…Between these, mutations in CHD2 are associated with neurological disorders, including intellectual disability, autism spectrum disorder, and epileptic encephalopathies [47–54], whereas loss of CHD1 in mouse embryonic stem cells leads to neural differentiation, suggesting CHD1 impairs neural fate [55]. Thus, we focused on CHD2 as the relevant homologue in the brain.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, the human CHD2 gene, but not human CHD1 is mutated in a variety of neurodevelopmental disorders [47–54]. CHD2, therefore, appears of special importance to the brain.…”

Section: Discussionmentioning

confidence: 99%

TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling

et al. 2017

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SUMMARY Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules. Conversely, upregulation of Chd1 restores nucleosomal dynamics, promotes normal induction of protective stress genes, and rescues stress sensitivity of TDP-43-expressing animals. TDP-43 mediated impairments are conserved in mammalian cells, and importantly the human orthologue CHD2 physically interacts with TDP-43 and is strikingly reduced in level in temporal cortex of human patient tissue. These findings indicate that TDP-43-mediated neurodegeneration causes impaired chromatin dynamics that prevents appropriate expression of protective genes through compromised function of the chromatin remodeler Chd1/CHD2. Enhancing chromatin dynamics may be a treatment approach to ALS/FTD.

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“…Tel: 403-955-7377; Email: bob.argiropoulos@albertahealthservices.ca insufficiency, in our review of the literature, at least 21 individuals with unique de novo heterozygous CHD2 mutations have thus far been described (Table 2). These individuals were ascertained from a cohort of patients with epileptic encephalopathies, ID, and ASD [10][11][12][13][14][15][16][17][18]. The phenotype of CHD2 mutation carriers is comparable to chromosome 15q26.1 microdeletion carriers, and includes mild-to-profound developmental delay with instances of regression, ID, ASD, behavioural problems and seizures.…”

Section: Segregating Sequence Changes Within Chd2 Are Associated Withmentioning

confidence: 99%

A Novel Genetic Syndrome Caused by Haploinsufficiency of CHD2, a Regulator of Chromatin Structure

Bone¹,

Argiropoulos²

2016

J Down Syndr Chr Abnorm

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CHD2 mutations are a rare cause of generalized epilepsy with myoclonic–atonic seizures

Cited by 34 publications

References 18 publications

Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing

Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing

TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling

A Novel Genetic Syndrome Caused by Haploinsufficiency of CHD2, a Regulator of Chromatin Structure

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