<i>CHD4</i> variants are associated with childhood idiopathic epilepsy with sinus arrhythmia

Liu, Xiaorong; Ye, Ting‐Ting; Zhang, Wenjun; Guo, Xuan; Wang, Jie; Huang, Shaoping; Xie, Longshan; Song, Xiaohang; Deng, Wei-Wen; Li, Bing‐Mei; He, Na; Wu, Qianyi; Zhuang, Min‐Zhi; Xu, Meng; Shi, Yi‐Wu; Su, Tao; Yi, Yong‐Hong; Liao, Wei‐Ping

doi:10.1111/cns.13692

Cited by 12 publications

(9 citation statements)

References 52 publications

(105 reference statements)

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“…None of them was discovered in the homozygotes of all population according to gnomAD (table 1). When the burden of recessive variants was analysed, the BSN variants in the present cohort were significantly more than the expected number by chance in the East Asian population (minor allele frequency from gnomAD (MAF) <0.005, p=2.316×10 5 ).…”

Section: Evaluating the Bsn Gene As A Novel Candidate Epilepsy Genementioning

confidence: 64%

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Variants inBSNgene associated with epilepsy with favourable outcome

Zhang

Wang

et al. 2022

J Med Genet

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BackgroundBSNgene encodes Bassoon, an essential protein to assemble the cytomatrix at the active zone of neurotransmitter release. This study aims to explore the relationship betweenBSNvariants and epilepsy.MethodsWhole-exome sequencing was performed in a cohort of 313 cases (trios) with epilepsies of unknown causes. Additional cases withBSNvariants were collected from China Epilepsy Gene V.1.0 Matching Platform. The Clinical Validity Framework of ClinGen was used to evaluate the relationship betweenBSNvariants and epilepsy.ResultsFour pairs of compound heterozygous variants and one cosegregating heterozygous missense variant inBSNwere identified in five unrelated families. These variants presented statistically higher frequency in the case cohort than in controls. Additional two de novo heterozygous nonsense variants and one cosegregating heterozygous missense variant were identified in three unrelated cases from the gene matching platform, which were not present in the Genome Aggregation Database. The missense variants tended to be located in C-terminus, including the two monoallelic missense variants. Protein modelling showed that at least one missense variant in each pair of compound heterozygous variants had hydrogen bond alterations. Clinically, two cases were diagnosed as idiopathic generalised epilepsy, two as focal epilepsy and the remaining four as epilepsy with febrile seizures plus. Seven out of eight probands showed infancy or childhood-onset epilepsy. Eight out of 10 affected individuals had a history of febrile convulsions. All the cases were seizure-free. The cases with monoallelic variants achieved seizure-free without treatment or under monotherapy, while cases with biallelic missense variants mostly required combined therapy. The evidence from ClinGen Framework suggested an association betweenBSNvariants and epilepsy.ConclusionTheBSNgene was potentially a novel candidate gene for epilepsy. The phenotypical severity was associated with the genotypes and the molecular subregional effects of the variants.

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Section: Evaluating the Bsn Gene As A Novel Candidate Epilepsy Genementioning

confidence: 64%

“…WES was performed with NextSeq2000 sequencing instruments (Illumina, San Diego, California, USA). Sequence alignment and variant calling were performed according to standard procedures as previously described 4 5 20. The potentially disease-causing variants were analysed with an individualised protocol.…”

Section: Methodsmentioning

confidence: 99%

Variants inBSNgene associated with epilepsy with favourable outcome

Zhang

Wang

et al. 2022

J Med Genet

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“…The proband's phenotype similarity score, calculated against the SIHIWES clinical synopsis at OMIM #617159, was low and without statistical significance [PhenSSc 1.29 (p = 0.1960; MaxSSc 3.02; MaxDiseaseSSc 3.64)]. Therefore, the clinical features reported in 44 patients with SIHIWES or CHD4-NDD were extensively revised and subdivided according to the pathogenic CHD4 variant (Tables S4 and S5) [19][20][21][22][23][24]. Indeed, the PhenSSC calculated against the revised clinical features reference list was 2.33, and near to statistical significance (p = 0.0587; MaxSSc 3.02; MaxDiseaseSSc 4.2) (Tables 1 and S6).…”

Section: Characterization Of the Genomic And Genetic Variants And Aff...mentioning

confidence: 99%

“…Therefore, this LoF CHD4 variant is the most likely cause of the patient's phenotype, establishing the diagnosis of SIHIWES or CHD4-NDD. The ratio between variants-patients with a specific clinical feature per total number of patients-variants (n = 44) with available data is reported [19][20][21][22][23][24]. Additional information is available in Tables S4-S6.…”

Section: Characterization Of the Genomic And Genetic Variants And Aff...mentioning

confidence: 99%

A Novel Frameshift CHD4 Variant Leading to Sifrim-Hitz-Weiss Syndrome in a Proband with a Subclinical Familial t(17;19) and a Large dup(2)(q14.3q21.1)

et al. 2022

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The genetic complexity of neurodevelopmental disorders (NDD), combined with a heterogeneous clinical presentation, makes accurate assessment of their molecular bases and pathogenic mechanisms challenging. Our purpose is to reveal the pathogenic variant underlying a complex NDD through identification of the “full” spectrum of structural genomic and genetic variants. Therefore, clinical phenotyping and identification of variants by genome and exome sequencing, together with comprehensive assessment of these and affected candidate genes, were carried out. A maternally-inherited familial translocation [t(17;19)(p13.1;p13.3)mat] disrupting the GSG1 like 2 gene (GSG1L2), a 3.2 Mb dup(2)(q14.3q21.1) encompassing the autosomal dominant OMIM phenotype-associated PROC and HS6ST1 gene, and a novel frameshift c.4442del, p.(Gly1481Valfs*21) variant within exon 30 of the Chromodomain helicase DNA binding protein 4 (CHD4) have been identified. Considering the pathogenic potential of each variant and the proband’s phenotype, we conclude that this case basically fits the Sifrim–Hitz–Weiss syndrome or CHD4-associated neurodevelopmental phenotype. Finally, our data highlight the need for identification of the “full” spectrum of structural genomic and genetic variants and of reverse comparative phenotyping, including unrelated patients with variants in same genes, for improved genomic healthcare of patients with NDD.

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“…Monogenic abnormalities only account for 2–8% of IGEs ( Weber and Lerche, 2008 ; Prasad et al, 2013 ). Exome-based genetic screening studies have demonstrated that over twenty genes were associated with IGEs, such as CACNA1H , CACNB4 , CASR , CHD4 , CLCN2 , EFHC1 , GABRD , GABRA1 , GABRG2 , GABRB3 , HCN2 , KCC2 , KCNMA1 , RORB , SCN1A , SLC12A5 , SLC2A1 , RYR 2, and THBS1 ( DiFrancesco et al, 2011 ; Striano et al, 2012 ; Kahle et al, 2014 ; Rudolf et al, 2016 ; Santolini et al, 2017 ; Wang et al, 2017 ; Abou El Ella et al, 2018 ; Li et al, 2018 ; Yap and Smyth, 2019 ; Chan et al, 2020 ; Liu et al, 2021 ). Recent studies also identified several copy number variants associated with IGEs, such as duplication at 8q21.13-q22.2 and microdeletions at 1q21.1, 15q11.2, 15q13.3, and 16p13.11 ( de Kovel et al, 2010 ; Kirov et al, 2013 ; Møller et al, 2013 ; Jähn et al, 2014 ; Rezazadeh et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

GRIN2A Variants Associated With Idiopathic Generalized Epilepsies

Liu

Lin

et al. 2021

Front. Mol. Neurosci.

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Objective: The objective of this study is to explore the role of GRIN2A gene in idiopathic generalized epilepsies and the potential underlying mechanism for phenotypic variation.Methods: Whole-exome sequencing was performed in a cohort of 88 patients with idiopathic generalized epilepsies. Electro-physiological alterations of the recombinant N-methyl-D-aspartate receptors (NMDARs) containing GluN2A mutants were examined using two-electrode voltage-clamp recordings. The alterations of protein expression were detected by immunofluorescence staining and biotinylation. Previous studies reported that epilepsy related GRIN2A missense mutations were reviewed. The correlation among phenotypes, functional alterations, and molecular locations was analyzed.Results: Three novel heterozygous missense GRIN2A mutations (c.1770A > C/p.K590N, c.2636A > G/p.K879R, and c.3199C > T/p.R1067W) were identified in three unrelated cases. Electrophysiological analysis demonstrated R1067W significantly increased the current density of GluN1/GluN2A NMDARs. Immunofluorescence staining indicated GluN2A mutants had abundant distribution in the membrane and cytoplasm. Western blotting showed the ratios of surface and total expression of the three GluN2A-mutants were significantly increased comparing to the wild type. Further analysis on the reported missense mutations demonstrated that mutations with severe gain-of-function were associated with epileptic encephalopathy, while mutations with mild gain of function were associated with mild phenotypes, suggesting a quantitative correlation between gain-of-function and phenotypic severity. The mutations located around transmembrane domains were more frequently associated with severe phenotypes and absence seizure-related mutations were mostly located in carboxyl-terminal domain, suggesting molecular sub-regional effects.Significance: This study revealed GRIN2A gene was potentially a candidate pathogenic gene of idiopathic generalized epilepsies. The functional quantitative correlation and the molecular sub-regional implication of mutations helped in explaining the relatively mild clinical phenotypes and incomplete penetrance associated with GRIN2A variants.

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CHD4 variants are associated with childhood idiopathic epilepsy with sinus arrhythmia

Cited by 12 publications

References 52 publications

Variants inBSNgene associated with epilepsy with favourable outcome

Variants inBSNgene associated with epilepsy with favourable outcome

A Novel Frameshift CHD4 Variant Leading to Sifrim-Hitz-Weiss Syndrome in a Proband with a Subclinical Familial t(17;19) and a Large dup(2)(q14.3q21.1)

GRIN2A Variants Associated With Idiopathic Generalized Epilepsies

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