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OBJECTIVE: Epilepsy with eyelid myoclonia (EEM) spectrum is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure-induced seizures with electroencephalographic paroxysms, and photosensitivity. Based on the specific clinical features, age at onset, and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF, RORB, and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic etiology of EEM. METHODS: We studied a cohort of 105 individuals by using whole exome sequencing. Individuals were divided into two groups: EEM- (isolated EEM) and EEM+ (EEM accompanied by intellectual disability [ID] or any other neurodevelopmental/psychiatric disorder). RESULTS: We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these, eight (five in CHD2, one in NEXMIF, one in SYNGAP1, and one in TRIM8) were found in the EEM+ subcohort (28.57%). Only one variant (IFIH1) was found in the EEM- subcohort (1.29%); however, because the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM- an established association. Burden analysis did not identify any single burdened gene or gene set. SIGNIFICANCE: Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with comorbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2, and the association of CHD2 with EEM+ can now be considered a reasonable gene-disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM- and IFIH1, are also reported. Although we provide robust evidence for gene variants associated with EEM+, the core genetic etiology of EEM- remains to be elucidated.
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Epilepsia Generalizada , Epilepsia Reflexa , Mioclonia , Humanos , Sequenciamento do Exoma , Helicase IFIH1 Induzida por Interferon/genética , Epilepsia Reflexa/genética , Eletroencefalografia , Pálpebras , Proteínas de Transporte/genética , Proteínas do Tecido Nervoso/genéticaRESUMO
Loss-of-function CHD2 (chromodomain helicase DNA-binding protein 2) mutations are associated with a spectrum of neurodevelopmental disorders often including early-onset generalized seizures, photosensitivity, and epileptic encephalopathies. Patients show psychomotor delay/intellectual disability (ID), autistic features, and behavior disorders, such as aggression and impulsivity. Most reported cases are sporadic with description of germline mosaicism only in two families. We detect the first case of parental gonosomal CHD2 mosaicism disclosed by two brothers showing mild ID, born to healthy parents. The eldest brother has a history of drug-controlled generalized tonic-clonic seizures and displays sleep disorder and aggressive behavior suggestive of Smith-Magenis syndrome (SMS). Analysis of brothers' DNAs by next-generation sequencing (NGS) custom gene panel for pediatric epilepsy and/or ID disclosed in both the same pathogenic CHD2 variant. Additional NGS experiment on genomic DNA from parents' peripheral blood and from buccal swab raised the suspicion of low-grade gonosomal mosaicism in the unaffected mother subsequently confirmed by digital polymerase chain reaction (dPCR). This report underlines as worthwhile CHD2 screening in individuals presenting ID/developmental delay, with/without epilepsy, and behavior and sleep disorders suggestive of SMS. Detecting a CHD2 variant should prime testing probands' parents by NGS coupled to dPCR on different tissues to exclude/confirm gonosomal mosaicism and define the recurrence risk.
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Mosaicismo , Irmãos , Síndrome de Smith-Magenis , Humanos , Masculino , Síndrome de Smith-Magenis/genética , Proteínas de Ligação a DNA/genética , Feminino , Deficiência Intelectual/genética , Criança , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Linhagem , Mutação/genética , Pré-Escolar , FenótipoRESUMO
CHD2 encodes the chromodomain helicase DNA-binding protein 2, an ATP-dependent enzyme that acts as a chromatin remodeler. CHD2 pathogenic variants have been associated with various early onset phenotypes including developmental and epileptic encephalopathy, self-limiting or pharmacoresponsive epilepsies and neurodevelopmental disorders without epilepsy. We reviewed 84 previously reported patients carrying 76 different CHD2 pathogenic or likely pathogenic variants and describe 18 unreported patients carrying 12 novel pathogenic or likely pathogenic variants, two recurrent likely pathogenic variants (in two patients each), three previously reported pathogenic variants, one gross deletion. We also describe a novel phenotype of adult-onset pharmacoresistant epilepsy, associated with a novel CHD2 missense likely pathogenic variant, located in an interdomain region. A combined review of previously published and our own observations indicates that although most patients (72.5%) carry truncating CHD2 pathogenic variants, CHD2-related phenotypes encompass a wide spectrum of conditions with developmental delay/intellectual disability (ID), including prominent language impairment, attention deficit hyperactivity disorder and autistic spectrum disorder. Epilepsy is present in 92% of patients with a median age at seizure onset of 2 years and 6 months. Generalized epilepsy types are prevalent and account for 75.5% of all epilepsies, with photosensitivity being a common feature and adult-onset nonsyndromic epilepsy a rare presentation. No clear genotype-phenotype correlation has emerged.
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Epilepsia , Transtornos do Neurodesenvolvimento , Proteínas de Ligação a DNA/genética , Eletroencefalografia , Epilepsia/genética , Humanos , Mutação , Transtornos do Neurodesenvolvimento/genética , FenótipoRESUMO
Epileptic encephalopathies (EE) are severe epilepsy syndromes characterized by multiple seizure types, developmental delay and even regression. This class of disorders are increasingly being identified as resulting from de novo genetic mutations including many identified mutations in the family of chromodomain helicase DNA binding (CHD) proteins. In particular, several de novo pathogenic mutations have been identified in the gene encoding chromodomain helicase DNA binding protein 2 (CHD2), a member of the sucrose nonfermenting (SNF-2) protein family of epigenetic regulators. These mutations in the CHD2 gene are causative of early onset epileptic encephalopathy, abnormal brain function, and intellectual disability. Our understanding of the mechanisms by which modification or loss of CHD2 cause this condition remains poorly understood. Here, we review what is known and still to be elucidated as regards the structure and function of CHD2 and how its dysregulation leads to a highly variable range of phenotypic presentations.
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Proteínas de Ligação a DNA/genética , Epilepsia Generalizada/genética , Predisposição Genética para Doença/genética , Deficiência Intelectual/genética , Mutação , Animais , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia Generalizada/patologia , Epilepsia Generalizada/fisiopatologia , Regulação da Expressão Gênica , Humanos , Deficiência Intelectual/fisiopatologiaRESUMO
Eyelid myoclonia with absences (EMA), also known as Jeavons syndrome (JS) is a childhood onset epileptic syndrome with manifestations involving a clinical triad of absence seizures with eyelid myoclonia (EM), photosensitivity (PS), and seizures or electroencephalogram (EEG) paroxysms induced by eye closure. Although a genetic contribution to this syndrome is likely and some genetic alterations have been defined in several cases, the genes responsible for have not been identified. In this review, patients diagnosed with EMA (or EMA-like phenotype) with a genetic diagnosis are summarized. Based on this, four genes could be associated to this syndrome (SYNGAP1, KIA02022/NEXMIF, RORB, and CHD2). Moreover, although there is not enough evidence yet to consider them as candidate for EMA, three more genes present also different alterations in some patients with clinical diagnosis of the disease (SLC2A1, NAA10, and KCNB1). Therefore, a possible relationship of these genes with the disease is discussed in this review.
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Epilepsia Tipo Ausência/genética , Doenças Genéticas Inatas/genética , Mioclonia/genética , HumanosRESUMO
BACKGROUND: The role of deleterious copy number variations in schizophrenia is well established while data regarding pathogenic variations remain scarce. We report for the first time a case of schizophrenia in a child with a pathogenic mutation of the chromodomain helicase DNA binding protein 2 (CHD2) gene. CASE PRESENTATION: The proband was the second child of unrelated parents. Anxiety and sleep disorders appeared at the age of 10 months. He presented febrile seizures and, at the age of 8, two generalized tonic-clonic seizures. At the age of 10, emotional withdrawal emerged, along with a flat affect, disorganization and paranoid ideation, without seizures. He began to talk and giggle with self. Eventually, the patient presented daily auditory and visual hallucinations. The diagnosis of childhood onset schizophrenia (DSM V) was then evoked. Brain imaging was unremarkable. Wakefulness electroencephalography showed a normal background and some bilateral spike-wave discharges that did not explain the psychosis features. A comparative genomic hybridization array (180 K, Agilent, Santa Clara, CA, USA) revealed an 867-kb 16p13.3 duplication, interpreted as a variant of unknown significance confirmed by a quantitative PCR that also showed its maternal inheritance. Risperidone (1,5 mg per day), led to clinical improvement. At the age of 11, an explosive relapse of epilepsy occurred with daily seizures of various types. The sequencing of a panel for monogenic epileptic disorders and Sanger sequencing revealed a de novo pathogenic heterozygous transition in CHD2 (NM_001271.3: c.4003G > T). CONCLUSIONS: This case underlines that schizophrenia may be, sometimes, underpinned by a Mendelian disease. It addresses the question of systematic genetic investigations in the presence of warning signs such as a childhood onset of the schizophrenia or a resistant epilepsy. It points that, in the absence of pathogenic copy number variation, the investigations should also include a search for pathogenic variations, which means that some of the patients with schizophrenia should benefit from Next Generation Sequencing tools. Last but not least, CHD2 encodes a member of the chromodomain helicase DNA-binding (CHD) family involved in chromatin remodeling. This observation adds schizophrenia to the phenotypic spectrum of chromodomain remodeling disorders, which may lead to innovative therapeutic approaches.
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Variações do Número de Cópias de DNA/genética , Proteínas de Ligação a DNA/genética , Esquizofrenia/genética , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Eletroencefalografia , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Fenótipo , Esquizofrenia/fisiopatologia , Convulsões Febris/genética , Convulsões Febris/patologiaRESUMO
Vagus nerve stimulation (VNS) is a surgical treatment available for patients affected by generalized refractory epilepsy. The authors report the case of a 15-year-old girl affected by CHD2-related myoclonic encephalopathy and BLM haploinsufficiency due to a deletion of 15q25.3q26.2 region, who suffered from secondary hemophagocytic lymphohistiocytosis (SHLH) after a VNS wound infection. SHLH has sporadically been described in epileptic patients. Based on indirect evidence that shows immune dysregulation in patients with CHD2 mutations and BLM mutations, we hypothesize that the genetic background of this patient may have played a critical role in the development of the syndrome.
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Epilepsia Resistente a Medicamentos , Epilepsias Mioclônicas , Epilepsia , Linfo-Histiocitose Hemofagocítica , Estimulação do Nervo Vago , Adolescente , Criança , Proteínas de Ligação a DNA , Feminino , Humanos , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/terapiaRESUMO
Cortical interneurons (cINs) modulate excitatory neuronal activity by providing local inhibition. During fetal development, several cIN subtypes derive from the medial ganglionic eminence (MGE), a transient ventral telencephalic structure. While altered cIN development contributes to neurodevelopmental disorders, the inaccessibility of human fetal brain tissue during development has hampered efforts to define molecular networks controlling this process. Here, we modified protocols for directed differentiation of human embryonic stem cells, obtaining efficient, accelerated production of MGE-like progenitors and MGE-derived cIN subtypes with the expected electrophysiological properties. We defined transcriptome changes accompanying this process and integrated these data with direct transcriptional targets of NKX2-1, a transcription factor controlling MGE specification. This analysis defined NKX2-1-associated genes with enriched expression during MGE specification and cIN differentiation, including known and previously unreported transcription factor targets with likely roles in MGE specification, and other target classes regulating cIN migration and function. NKX2-1-associated peaks were enriched for consensus binding motifs for NKX2-1, LHX, and SOX transcription factors, suggesting roles in coregulating MGE gene expression. Among the NKX2-1 direct target genes with cIN-enriched expression was CHD2, which encodes a chromatin remodeling protein mutated to cause human epilepsies. Accordingly, CHD2 deficiency impaired cIN specification and altered later electrophysiological function, while CHD2 coassociated with NKX2-1 at cis-regulatory elements and was required for their transactivation by NKX2-1 in MGE-like progenitors. This analysis identified several aspects of gene-regulatory networks underlying human MGE specification and suggested mechanisms by which NKX2-1 acts with chromatin remodeling activities to regulate gene expression programs underlying cIN development.
Assuntos
Diferenciação Celular , Córtex Cerebral/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Embrionárias Humanas/metabolismo , Interneurônios/metabolismo , Linhagem Celular , Córtex Cerebral/citologia , Proteínas de Ligação a DNA/genética , Células-Tronco Embrionárias Humanas/citologia , Humanos , Interneurônios/citologia , Fator Nuclear 1 de Tireoide/genética , Fator Nuclear 1 de Tireoide/metabolismoRESUMO
Recent large-scale exome sequencing studies have identified mutations in several members of the CHD (Chromodomain Helicase DNA-binding protein) gene family in neurodevelopmental disorders. Mutations in the CHD2 gene have been linked to developmental delay, intellectual disability, autism and seizures, CHD8 mutations to autism and intellectual disability, whereas haploinsufficiency of CHD7 is associated with executive dysfunction and intellectual disability. In addition to these neurodevelopmental features, a wide range of other developmental defects are associated with mutants of these genes, especially with regards to CHD7 haploinsufficiency, which is the primary cause of CHARGE syndrome. Whilst the developmental expression of CHD7 has been reported previously, limited information on the expression of CHD2 and CHD8 during development is available. Here, we compare the expression patterns of all three genes during mouse development directly. We find high, widespread expression of these genes at early stages of development that gradually becomes restricted during later developmental stages. Chd2 and Chd8 are widely expressed in the developing central nervous system (CNS) at all stages of development, with moderate expression remaining in the neocortex, hippocampus, olfactory bulb and cerebellum of the postnatal brain. Similarly, Chd7 expression is seen throughout the CNS during late embryogenesis and early postnatal development, with strong enrichment in the cerebellum, but displays low expression in the cortex and neurogenic niches in early life. In addition to expression in the brain, novel sites of Chd2 and Chd8 expression are reported. These findings suggest additional roles for these genes in organogenesis and predict that mutation of these genes may predispose individuals to a range of other, non-neurological developmental defects.
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Transtorno Autístico/genética , Proteínas de Ligação a DNA/biossíntese , Transcriptoma , Animais , Embrião de Mamíferos , Camundongos , Neurogênese/genética , FenótipoRESUMO
Pathogenic variants in CHD2 (chromodomain helicase DNA-binding protein 2) have been reported in neurodevelopmental disorders with a broad spectrum of phenotypic variability, ranging from mild intellectual disability to atonic-myoclonic epilepsy. However, given the paucity of reported cases the extent of this phenotypic spectrum is currently unknown. Furthermore, all confirmed pathogenic CHD2 variants reported to date have been de novo, preventing the study of intrafamilial phenotypic heterogeneity and creating ambiguity regarding recurrence risk, penetrance, and expressivity. Here, we report the first known case of an inherited pathogenic CHD2 variant in affected mother and daughter. This case demonstrates intrafamilial phenotypic heterogeneity and confirms potential heritability of CHD2-related neurodevelopmental disorders.
Assuntos
Proteínas de Ligação a DNA/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Adulto , Pré-Escolar , Eletroencefalografia , Humanos , Pessoa de Meia-Idade , Mães , Núcleo Familiar , Fenótipo , Adulto JovemRESUMO
Although 15N- and 13C-based chemical exchange saturation transfer (CEST) experiments have assumed an important role in studies of biomolecular conformational exchange, 1H CEST experiments are only beginning to emerge. We present a methyl-TROSY 1H CEST experiment that eliminates deleterious 1H-1H NOE dips so that CEST profiles can be analyzed robustly to extract methyl proton chemical shifts of rare protein conformers. The utility of the experiment, along with a version that is optimized for 13CHD2 labeled proteins, is established through studies of exchanging protein systems. A comparison between methyl 1H CEST and methyl 1H CPMG approaches is presented to highlight the complementarity of the two experiments.
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Ressonância Magnética Nuclear Biomolecular/métodos , Proteínas/química , Metilação , Fatores de TempoRESUMO
Germline mosaicism for a novel missense variant p.Thr645Met located in the SNF2-related ATP dependent helicase domain of CHD2 in 2 affected siblings with autism spectrum disorder.
Assuntos
Transtorno do Espectro Autista/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Mosaicismo , Mutação de Sentido Incorreto , Herança Paterna , Sequência de Aminoácidos , Transtorno do Espectro Autista/fisiopatologia , Criança , Exoma , Feminino , Expressão Gênica , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Modelos Moleculares , Linhagem , Estrutura Secundária de Proteína , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Irmãos , Adulto JovemRESUMO
Chromodomain helicase DNA-binding protein 2 (CHD2) is an ATPase and a member of the SNF2-like family of helicase-related enzymes. Although deletions of CHD2 have been linked to developmental defects in mice and epileptic disorders in humans, little is known about its biochemical and cellular activities. In this study, we investigate the ATP-dependent activity of CHD2 and show that CHD2 catalyzes the assembly of chromatin into periodic arrays. We also show that the N-terminal region of CHD2, which contains tandem chromodomains, serves an auto-inhibitory role in both the DNA-binding and ATPase activities of CHD2. While loss of the N-terminal region leads to enhanced chromatin-stimulated ATPase activity, the N-terminal region is required for ATP-dependent chromatin remodeling by CHD2. In contrast, the C-terminal region, which contains a putative DNA-binding domain, selectively senses double-stranded DNA of at least 40 base pairs in length and enhances the ATPase and chromatin remodeling activities of CHD2. Our study shows that the accessory domains of CHD2 play central roles in both regulating the ATPase domain and conferring selectivity to chromatin substrates.
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Adenosina Trifosfatases/genética , Montagem e Desmontagem da Cromatina/genética , Cromatina/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Histonas/genética , Adenosina Trifosfatases/metabolismo , Sequência de Aminoácidos , Animais , Baculoviridae/genética , Sítios de Ligação , Cromatina/química , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Histonas/metabolismo , Humanos , Dados de Sequência Molecular , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Células Sf9 , SpodopteraRESUMO
Methyl groups have emerged as powerful probes of protein dynamics with timescales from picoseconds to seconds. Typically, studies involving high molecular weight complexes exploit (13)CH3- or (13)CHD2-labeling in otherwise highly deuterated proteins. The (13)CHD2 label offers the unique advantage of providing (13)C, (1)H and (2)H spin probes, however a disadvantage has been the lack of an experiment to record (13)C Carr-Purcell-Meiboom-Gill relaxation dispersion that monitors millisecond time-scale dynamics, implicated in a wide range of biological processes. Herein we develop an experiment that eliminates artifacts that would normally result from the scalar coupling between (13)C and (2)H spins that has limited applications in the past. The utility of the approach is established with a number of applications, including measurement of ms dynamics of a disease mutant of a 320 kDa p97 complex.
Assuntos
Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Simulação de Dinâmica Molecular , Ressonância Magnética Nuclear Biomolecular , Conformação Proteica , Proteínas/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Deutério , Ressonância Magnética Nuclear Biomolecular/métodos , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
An NMR experiment for quantifying slow (millisecond) time-scale exchange processes involving the interconversion between visible ground state and invisible, conformationally excited state conformers is presented. The approach exploits chemical exchange saturation transfer (CEST) and makes use of (13)CHD2 methyl group probes that can be readily incorporated into otherwise highly deuterated proteins. The methodology is validated with an application to a G48A Fyn SH3 domain that exchanges between a folded conformation and a sparsely populated and transiently formed unfolded ensemble. Experiments on a number of different protein systems, including a 360 kDa half-proteasome, establish that the sensitivity of this (13)CHD2 (13)C-CEST technique can be upwards of a factor of 5 times higher than for a previously published (13)CH3 (13)C-CEST approach (Bouvignies and Kay in J Biomol NMR 53:303-310, 2012), suggesting that the methodology will be powerful for studies of conformational exchange in high molecular weight proteins.
Assuntos
Ressonância Magnética Nuclear Biomolecular/métodos , Conformação Proteica , Proteínas/química , Peso MolecularRESUMO
Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy with a heterogeneous etiology. In this study, we aimed to explore the role of CHD2 in LGS, as CHD2 mutations have been described recently in various epileptic encephalopathies. We have previously identified one patient with a large deletion affecting the CHD2 gene in a group of 22 patients with LGS or LGS-like epilepsy. In the remaining 17 patients without known etiology, Sanger sequencing revealed a de novo 1-bp duplication in the CHD2 gene in another patient. This mutation leads to a frameshift and, consequently, a premature stop codon 49bp downstream of the mutation. The patient had prominent myoclonic seizures and photosensitivity, thus, sharing phenotypic features with previously reported patients with CHD2-related epilepsy. In our original material of 22 patients with LGS features, we have now found two (9%) with mutations in the CHD2 gene. Our findings suggest that CHD2 mutations are important in the etiological spectrum of LGS.
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Proteínas de Ligação a DNA/genética , Síndrome de Lennox-Gastaut/genética , Adulto , Encéfalo/fisiopatologia , Eletroencefalografia , Feminino , Humanos , Síndrome de Lennox-Gastaut/fisiopatologia , Masculino , MutaçãoRESUMO
INTRODUCTION: Increasing evidence reveals critical roles for CHD2 in children with developmental and epileptic encephalopathy. OBJECTIVES: The aim was to present clinical analysis results of five cases with CHD2 mutations and 157 reported cases with non-copy number variations (non-CNV) of CHD2. METHODS: This study recruited pediatric epilepsy patients with CHD2 mutations and clinical data from November 2016 to October 2023 in the Linyi People's Hospital, China. Whole-exome and gene panel sequencing were employed to find mutations. The HGMD and PubMed databases were examined for documented cases that had CHD2 mutations. RESULTS: This study reports five cases with CHD2 mutations: c.3543T > A, c.1850A > G, c.2536C > T, c.4233_4236del, c.3782G > C. Three novel mutations (c.3543T > A, c.1850A > G, c.2536C > T) have never been reported. c.4233_4236del has been reported in three cases, indicating that this locus may be a mutation hotspot. c.3782G > C has been reported in one case. All five patients had seizures before the age of four. Three patients had varying degrees of developmental delay, and four patients had varying degrees of intellectual disability. All of them had controlled seizures after Valproic acid (VPA) monotherapy or VPA in combination with other medications. Furthermore, we reviewed 157 reported cases having non-CNV mutations of CHD2. Most mutations of these cases were de novo. Epilepsy, developmental delay, and intellectual disability were the typical clinical phenotypes. We also found a significant clustering of the mutations near the C-terminus of the CHD2 protein (P < 0.001). CONCLUSION: This study reports new CHD2 genotypes and analyzes reported CHD2 mutation cases. Given its significance in epileptic encephalopathies, research on the CHD2 gene may provide new insights into epileptogenesis.
RESUMO
BACKGROUND: The chromodomain helicase DNA-binding protein 2 (CHD2) is a member of the ATP-dependent chromatin remodelling family of proteins, which are critical for the assembly and regulation of chromatin. De novo variants and deletions in the CHD2 gene have been associated with childhood-onset developmental and epileptic encephalopathies type 94 (DEE 94). This study reports a novel deleterious de novo heterozygous frameshift insertion variant in the CHD2 gene. METHODS: The causative variant was diagnosed using whole-exome sequencing. Sanger sequencing and cosegregation analysis were applied to confirm the candidate variant. Multiple in silico analysis tools were employed to interpret the variant using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. RESULTS: A de novo deleterious variant, NM_001271.4:c.1570dup (NP_001262.3:p.Ser524PhefsTer30), in the CHD2 gene, was identified in a 16-year-old boy with an intellectual and developmental disability, seizures and speech problems. The de novo occurrence of the variant was confirmed by segregation analysis in the family. CONCLUSION: The findings of this study expand the existing knowledge of variants of the CHD2 gene and provide a detailed phenotype associated with this gene. These data could have implications for genetic diagnosis and counselling in similar conditions. Moreover, this information could be useful for therapeutic purposes, including the proper administration of medication to control epilepsy.
Assuntos
Deficiências do Desenvolvimento , Fala , Adolescente , Humanos , Masculino , Deficiências do Desenvolvimento/genética , Proteínas de Ligação a DNA/genética , Mutação , ConvulsõesRESUMO
OBJECTIVE: This study investigated sex-specific pathogenesis mechanisms in Alzheimer's disease (AD) using single-nucleus RNA sequencing (snRNA-seq) data. METHODS: Data from the Gene Expression Omnibus (GEO) were searched using terms "Alzheimer's Disease", "single cell", and "Homo sapiens". Studies excluding APOE E4 and including comprehensive gender information with 10× sequencing methods were selected, resulting in GSE157827 and GSE174367 datasets from human prefrontal cortex samples. Sex-stratified analyses were conducted on these datasets, and the outcomes of the analysis for GSE157827 were compared with those of GSE174367. The findings were validated using expression profiling from the mouse dataset GSE85162. Furthermore, real-time PCR experiments in mice further confirmed these findings. The Seurat R package was used to identify cell types, and batch effects were mitigated using the Harmony R package. Cell proportions by sex were compared using the Mann-Whitney-Wilcoxon test, and gene expression variability was displayed with an empirical cumulative distribution plot. Differentially expressed genes were identified using the FindMarkers function with the MAST test. Transcription factors were analyzed using the RcisTarget R package. RESULTS: Seven cell types were identified: astrocytes, endothelial cells, excitatory neurons, inhibitory neurons, microglia, oligodendrocytes, and oligodendrocyte progenitor cells. Additionally, five distinct subpopulations of both endothelial and microglial cells were also identified, respectively. Key findings included: (1) In endothelial cells, genes involved in synapse organization, such as Insulin Like Growth Factor 1 Receptor (IGF1R) and Fms Related Receptor Tyrosine Kinase 1(FLT1), showed higher expression in females with AD. (2) In microglial cells, genes in the ribosome pathway exhibited higher expression in males without AD compared to females (with or without AD) and males with AD. (3) Chromodomain Helicase DNA Binding Protein 2 (CHD2) negatively regulated gene expression in the ribosome pathway in male microglia, suppressing AD, this finding was further validated in mice. (4) Differences between Asians and Caucasians were observed based on sex and disease status stratification. CONCLUSIONS: IGF1R and FLT1 in endothelial cells contribute to AD in females, while CHD2 negatively regulates ribosome pathway gene expression in male microglia, suppressing AD in humans and mice.
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Doença de Alzheimer , Células Endoteliais , Microglia , Receptor IGF Tipo 1 , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Feminino , Animais , Masculino , Microglia/metabolismo , Humanos , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Camundongos , Células Endoteliais/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores Sexuais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Córtex Pré-Frontal/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Epilepsy with eyelid myoclonia (EM) or Jeavons syndrome (JS) is an epileptic syndrome related to the spectrum of genetic generalized epilepsies (GGE). We report two untreated children on which EEGs were performed several hours after a generalized tonic-clonic seizure (GTCS). These showed a unilateral, nearly continuous posterior slowing. This slow-wave activity was associated with contralateral epileptiform activity in one case, while in the second case, it was associated with an ipsilateral activity. However, in the latter child, a few months later an independent focus on the contralateral side was observed. A diagnosis of focal occipital lobe epilepsy was proposed in both cases, and one child underwent a left occipital lobectomy at 3.5 years of age. Despite surgery, absences with EM persisted in this child, and a marked photosensitivity to photic stimulation was observed two years later. The focal slow wave activity of one occipital lobe several hours after a GTCS in these two subjects was in favor of a focal onset preceding the generalization. The EEG evidence for independent left and right posterior focus in these two cases, the persistence of EM, and the development of a marked photosensitivity to photic stimulation in the child who underwent an occipital lobectomy, allow us to suggest that JS is associated with a network of bi-occipital hyperexcitability that rapidly engages bilaterally to produce generalized seizures.