New <i>SMARCA2</i> mutation in a patient with Nicolaides–Baraitser syndrome and myoclonic astatic epilepsy

Tang, Shan; Hughes, Elaine; Lascelles, Karine; Simpson, Michael A.; Pal, DK

doi:10.1002/ajmg.a.37935

Cited by 16 publications

(23 citation statements)

References 16 publications

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“…It is one of six genes that encode the SWItch/sucrose nonfermentable like chromatin remodeling complex and alters chromatin structure through ATP hydrolysis. Subject 3003 301, with a de novo p.Gln1241Glu SMARCA2 variant, was subsequently identified as also having clinical features compatible with a diagnosis of Nicolaides‐Baraitser syndrome along with MAE 23 …”

Section: Resultsmentioning

confidence: 99%

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Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

et al. 2020

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Objective: We aimed to describe the extent of neurodevelopmental impairments and identify the genetic etiologies in a large cohort of patients with epilepsy with myoclonic atonic seizures (MAE). Methods: We deeply phenotyped MAE patients for epilepsy features, intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder using standardized neuropsychological instruments. We performed exome analysis (whole exome sequencing) filtered on epilepsy and neuropsychiatric gene sets to identify genetic etiologies. Results: We analyzed 101 patients with MAE (70% male). The median age of seizure onset was 34 months (range = 6-72 months). The main seizure types were myoclonic atonic or atonic in 100%, generalized tonic-clonic in 72%, myoclonic in 69%, absence in 60%, and tonic seizures in 19% of patients. We observed intellectual disability in 62% of patients, with extremely low adaptive behavioral scores in 69%. In addition, 24% exhibited symptoms of autism and 37% exhibited attention-deficit/hyperactivity symptoms. We discovered pathogenic variants in 12 (14%) of 85 patients, including five previously published patients. These were pathogenic genetic variants in SYNGAP1 (n = 3), KIAA2022 (n = 2), and SLC6A1 (n = 2), as well as KCNA2, SCN2A, STX1B, KCNB1, and MECP2 (n = 1 each). We also identified three new candidate genes, ASH1L, CHD4, and SMARCA2 in one patient each. Significance: MAE is associated with significant neurodevelopmental impairment.MAE is genetically heterogeneous, and we identified a pathogenic genetic etiology in 14% of this cohort by exome analysis. These findings suggest that MAE is a manifestation of several etiologies rather than a discrete syndromic entity. K E Y W O R D S Doose syndrome, epilepsy/seizures, genetics, myoclonic astatic epilepsy SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: Tang S, Addis L, Smith A, et al; EuroEPINOMICS-RES Consortium. Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures. Epilepsia. 2020;61:995-1007. https://

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Section: Resultsmentioning

confidence: 99%

“…Here, we set out to provide a multifaceted analysis of the condition and describe deep phenotyping and exome sequencing in a cohort of 101 MAE patients. We present assumed pathogenic variants in seven unpublished and five previously described cases from single gene discovery studies 13–15,18,19,23 …”

Section: Introductionmentioning

confidence: 99%

Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

et al. 2020

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“…Two of these variants were proximal to that of SMARCA_12 (i.e. closer to the ATPase/ helicase domain); one just outside the domain [24], the other approximately 30 amino acids distal to it [23]. Both of these patients are described to have a typical NCBRS phenotype (Additional file 1: Table S14).…”

Section: Discussionmentioning

confidence: 99%

“…The authors noted that all pathogenic sequence variants were de novo heterozygous missense variants in the ATPase/helicase domain, indicating that these changes may not impair BAF complex assembly but rather disrupt ATPase function possibly acting in a dominant negative manner [17]. To date, the vast majority of SMARCA2 pathogenic variants in individuals with NCBRS have mapped to the ATPase/C-terminal helicase domain [17]; only two cases with typical NCBRS phenotypes have been reported to harbor missense variants distal to this domain [23,24]. Sequence variants in other BAF complex genes are associated with other neurodevelopmental disorders including SMARCC1/2, PBRM1, ARID1A/B and SMARCA4 in ASD, PBRM1 and ARID1B in schizophrenia, SMARCB1 in Kleefstra syndrome, and ARID1A/B, SMARCA4, SMARCB1, and SMARCE1 Coffin-Siris syndrome (CSS) [19,21].…”

Section: Introductionmentioning

confidence: 99%

New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome

Chater‐Diehl¹,

Ejaz²,

Cytrynbaum³

et al. 2019

BMC Med Genomics

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Background: Nicolaides-Baraitser syndrome (NCBRS) is a neurodevelopmental disorder caused by pathogenic sequence variants in SMARCA2 which encodes the catalytic component of the chromatin remodeling BAF complex. Pathogenic variants in genes that encode epigenetic regulators have been associated with genome-wide changes in DNA methylation (DNAm) in affected individuals termed DNAm signatures. Methods: Genome-wide DNAm was assessed in whole-blood samples from the individuals with pathogenic SMARCA2 variants and NCBRS diagnosis (n = 8) compared to neurotypical controls (n = 23) using the Illumina MethylationEPIC array. Differential methylated CpGs between groups (DNAm signature) were identified and used to generate a model enabling classification variants of uncertain significance (VUS; n = 9) in SMARCA2 as "pathogenic" or "benign". A validation cohort of NCBRS cases (n = 8) and controls (n = 96) demonstrated 100% model sensitivity and specificity. Results: We identified a DNAm signature of 429 differentially methylated CpG sites in individuals with NCBRS. The genes to which these CpG sites map are involved in cell differentiation, calcium signaling, and neuronal function consistent with NCBRS pathophysiology. DNAm model classifications of VUS were concordant with the clinical phenotype; those within the SMARCA2 ATPase/helicase domain classified as "pathogenic". A patient with a mild neurodevelopmental NCBRS phenotype and a VUS distal to the ATPase/helicase domain did not score as pathogenic, clustering away from cases and controls. She demonstrated an intermediate DNAm profile consisting of one subset of signature CpGs with methylation levels characteristic of controls and another characteristic of NCBRS cases; each mapped to genes with ontologies consistent with the patient's unique clinical presentation.

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“…Apart from moderate-to-profound intellectual disability [ 11 ], neurological involvement in the syndrome may include seizures in up to two-thirds of patients, like in this one [ 12 ]. However, this female individual did not present with all of the features of the typical NCBRS craniofacial phenotype.…”

Section: Discussionmentioning

confidence: 99%

A SMARCA2 Mutation in the First Case Report of Nicolaides-Baraitser Syndrome in Latin America: Genotype-Phenotype Correlation

Sánchez

Rojas

2017

Case Reports in Genetics

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Nicolaides-Baraitser syndrome (NCBRS) is a rare and well-recognized entity that was first described in 1993, with a prevalence that is currently not known. It is recognized as a distinctive entity, with some variability in its signs and symptoms. The most important characteristics include intellectual disability, peculiar facial features including sparse scalp hair, coarse facial features, low frontal hairline, and microcephaly, and seizures. Additional features may include epicanthic folds, thin upper lip vermilion with thick lower lip vermilion, skeletal abnormalities, and severe language impairment. The disorder is inherited in an autosomal dominant manner caused by de novo mutations in the SMARCA2 gene, with most being missense mutations. We report a young adult patient with NCBRS and, to our knowledge, the first case report of the syndrome in Latin America with a confirmed molecular diagnosis and a mild-to-moderate phenotype.

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New SMARCA2 mutation in a patient with Nicolaides–Baraitser syndrome and myoclonic astatic epilepsy

Cited by 16 publications

References 16 publications

Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome

A SMARCA2 Mutation in the First Case Report of Nicolaides-Baraitser Syndrome in Latin America: Genotype-Phenotype Correlation

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