Epilepsy features in ARID1B‐related Coffin‐Siris syndrome

Proietti, Jacopo; Amadori, Elisabetta; Striano, Pasquale; Ricci, Emilia; Cordelli, Duccio Maria; Bana, Cristina; Dilena, Robertino; Gardella, Elena; Pisani, Francesco; Barco, Tommaso Lo; Fiorini, Elena; Fontana, Elena; Darra, Francesca; Bernardina, Bernardo Dalla; Cantalupo, Gaetano

doi:10.1684/epd.2021.1356

Cited by 3 publications

(1 citation statement)

References 16 publications

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“…Finally, human patients with Arid1b haploinsufficiency have increased susceptibility to seizures, suggesting hyperexcitability of neural circuits (van der Sluijs et al, 2019; Proietti et al, 2021). Consistent with human studies, previous work found that mice with whole-body Arid1b haploinsufficiency exhibit higher susceptibility to seizures induced by a lethal dose of pentylenetetrazol (Ellegood et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

Arid1bhaploinsufficiency in pyramidal neurons causes cellular and circuit changes in neocortex but is not sufficient to produce behavioral or seizure phenotypes

Marshall,

Hanson,

Boyle

et al. 2024

Preprint

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Arid1bis a high confidence risk gene for autism spectrum disorder that encodes a subunit of a chromatin remodeling complex expressed in neuronal progenitors. Haploinsufficiency causes a broad range of social, behavioral, and intellectual disability phenotypes, including Coffin-Siris syndrome. Recent work using transgenic mouse models suggests pathology is due to deficits in proliferation, survival, and synaptic development of cortical neurons. However, there is conflicting evidence regarding the relative roles of excitatory projection neurons and inhibitory interneurons in generating abnormal cognitive and behavioral phenotypes. Here, we conditionally knocked out either one or both copies ofArid1bfrom excitatory projection neuron progenitors and systematically investigated the effects on intrinsic membrane properties, synaptic physiology, social behavior, and seizure susceptibility. We found that disruptingArid1bexpression in excitatory neurons alters their membrane properties, including hyperpolarizing action potential threshold; however, these changes depend on neuronal subtype. Using paired whole-cell recordings, we found increased synaptic connectivity rate between projection neurons. Furthermore, we found reduced strength of excitatory synapses to parvalbumin (PV)-expression inhibitory interneurons. These data suggest an increase in the ratio of excitation to inhibition. However, the strength of inhibitory synapses from PV interneurons to excitatory neurons was enhanced, which may rebalance this ratio. Indeed,Arid1bhaploinsufficiency in projection neurons was insufficient to cause social deficits and seizure phenotypes observed in a preclinical germline haploinsufficient mouse model. Our data suggest that while excitatory projection neurons likely contribute to autistic phenotypes, pathology in these cells is not the primary cause.

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Section: Resultsmentioning

confidence: 99%

Arid1bhaploinsufficiency in pyramidal neurons causes cellular and circuit changes in neocortex but is not sufficient to produce behavioral or seizure phenotypes

Marshall,

Hanson,

Boyle

et al. 2024

Preprint

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Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike–Wave Activation in Sleep (D/EE‐SWAS)

Viswanathan,

Oliver,

Regan

et al. 2024

Annals of Neurology

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ObjectiveTo understand the etiological landscape and phenotypic differences between 2 developmental and epileptic encephalopathy (DEE) syndromes: DEE with spike–wave activation in sleep (DEE‐SWAS) and epileptic encephalopathy with spike–wave activation in sleep (EE‐SWAS).MethodsAll patients fulfilled International League Against Epilepsy (ILAE) DEE‐SWAS or EE‐SWAS criteria with a Core cohort (n = 91) drawn from our Epilepsy Genetics research program, together with 10 etiologically solved patients referred by collaborators in the Expanded cohort (n = 101). Detailed phenotyping and analysis of molecular genetic results were performed. We compared the phenotypic features of individuals with DEE‐SWAS and EE‐SWAS. Brain‐specific gene co‐expression analysis was performed for D/EE‐SWAS genes.ResultsWe identified the etiology in 42/91 (46%) patients in our Core cohort, including 29/44 (66%) with DEE‐SWAS and 13/47 (28%) with EE‐SWAS. A genetic etiology was identified in 31/91 (34%). D/EE‐SWAS genes were highly co‐expressed in brain, highlighting the importance of channelopathies and transcriptional regulators. Structural etiologies were found in 12/91 (13%) individuals. We identified 10 novel D/EE‐SWAS genes with a range of functions: ATP1A2, CACNA1A, FOXP1, GRIN1, KCNMA1, KCNQ3, PPFIA3, PUF60, SETD1B, and ZBTB18, and 2 novel copy number variants, 17p11.2 duplication and 5q22 deletion. Although developmental regression patterns were similar in both syndromes, DEE‐SWAS was associated with a longer duration of epilepsy and poorer intellectual outcome than EE‐SWAS.InterpretationDEE‐SWAS and EE‐SWAS have highly heterogeneous genetic and structural etiologies. Phenotypic analysis highlights valuable clinical differences between DEE‐SWAS and EE‐SWAS which inform clinical care and prognostic counseling. Our etiological findings pave the way for the development of precision therapies. ANN NEUROL 2024

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Genetic epilepsy and role of mutation variants in 27 epileptic children: results from a “single tertiary centre” and literature review

Pavone,

Avola,

Oliva

et al. 2024

AIMSMEDS

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<sec><title>Aim and scope</title>The wide use of next-generation sequencing has allowed professionals to reach relevant progress in the medical field including diagnoses, prognoses, and genetic counselling and to help in recognizing the pathogenic mechanisms which underlie several epileptic disorders. Genetic epilepsy refers to a disorder in which genetic mutations are recognized as the primary cause of epileptic seizures in the patients. Various types of epilepsy have been highlighted alongside a clear etiologic relationship with genetic mutations; however, for a select number of patients, some doubts remain on the role played by the variant mutations, as well as the adverse pathologic events which may interfere with the clinical manifestations. In this study, twenty-seven children affected by epileptic seizures are reported, with the aim to describe the clinical and neurological involvement presented by the children according to the genes and variant mutations, and to compare the neurological signs observed in these children with those reported in children with similar genetic mutations. Additionally, the roles played by single or associated variants on the clinical expression of the affected children are discussed.</sec><sec><title>Material and methods</title>A retrospective observational study was conducted on the gene mutations observed in 27 children affected by a clinical history and diagnosis of epilepsy, alongside an electroencephalographic analysis performed with the Pediatric Department of the University-Hospital S. Marco during the years ranging from January 2020 to January 2022. A genetic analysis was performed using an array comparative genomic hybridization (array CGH), a gene panel for epilepsy, Whole Exome Sequencing (WES), and a single nucleotide polymorphism (SNP) array.</sec><sec><title>Results</title>Nineteen children showed a single nucleotide variant, eight children carried two or more gene mutations in different genes, and one child was not reported. In this study, we identified a total of thirty-six gene mutations, where seventeen were de novo mutations, and twenty-two had either a maternal or paternal inheritance. The genes in which one or more allelic variants were found included <italic>GRIN2A</italic>, <italic>GABRA1</italic>, <italic>SCN2A1,</italic> <italic>KCNT1</italic>, <italic>PCDH19</italic>, <italic>SCN8A</italic>, <italic>KCNK4</italic>, <italic>SLC2A1</italic>, <italic>DNM1</italic>, <italic>ARID1B</italic>, <italic>WWOX</italic>, <italic>GABRG2,</italic> and others.</sec><sec><title>Conclusions</title>Genetic analyses are recognized to have a central role in the diagnostic process of children with epileptic seizures, alongside their family history, and clinical, neuroradiologic, and neurophysiologic examinations. The gene mutation anomalies reported in this study may be useful to be included in the wide field of factors related to epileptic seizures in children. The roles played by single or associated variant mutations in the clinical expression of the affected epileptic children remain difficult to be defined. Moreover, other factors such as pre-, peri-, and post-natal adverse events may negatively interfere with the severity of the clinical manifestations.</sec>

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Epilepsy features in ARID1B‐related Coffin‐Siris syndrome

Cited by 3 publications

References 16 publications

Arid1bhaploinsufficiency in pyramidal neurons causes cellular and circuit changes in neocortex but is not sufficient to produce behavioral or seizure phenotypes

Arid1bhaploinsufficiency in pyramidal neurons causes cellular and circuit changes in neocortex but is not sufficient to produce behavioral or seizure phenotypes

Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike–Wave Activation in Sleep (D/EE‐SWAS)

Genetic epilepsy and role of mutation variants in 27 epileptic children: results from a “single tertiary centre” and literature review

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