The evolving features of Nicolaides–Baraitser syndrome – a clinical report of a 20‐year follow‐up

Ejaz, Resham; Babul‐Hirji, Riyana; Chitayat, David

doi:10.1002/ccr3.425

Cited by 17 publications

(14 citation statements)

References 9 publications

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“…Clinically, the NCBRS cases encompassed the variable spectrum of disorder severity (detailed clinical data found in Additional file 2: Table S1). SMARCA2_5 and SMARCA2_11 have been previously published as NBS24 and NBS26 [17], SMARCA2_1 has also been previously described by our group [29]. Unique features noted in the cohort included ophthalmologic abnormalities, such as unilateral retinal detachment in SMARCA2_1, bilateral infantile glaucoma in SMARCA2_4 and myopia in SMARCA2_12 and SMARCA2_14.…”

Section: Research Participantssupporting

confidence: 57%

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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Section: Research Participantssupporting

confidence: 57%

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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“…Among the 70 mutations reported in NCBRS patients, one is an in-frame 6-bp deletion, two are in-frame multi-exon deletions affecting the ATPase domain, and 62 are missense mutations. Of the 62 missense mutations, 60 are mapped to the ATPase domain, one is proximal but outside the ATPase domain, and the other is in the bromo domain (Van Houdt et al, 2012 ; Sousa et al, 2014 ; Ejaz et al, 2016 ). Notably, deletions encompassing human BRM locus have not been found in NCBRS (Christ et al, 1999 ).…”

Section: Role Of Baf Complex In Neurodevelopmental Disordersmentioning

confidence: 99%

“…Because null BRM KO mice do not show major developmental defects (Koga et al, 2009 ; Magnani and Cabot, 2009 ) and none of the identified mutations cause truncated proteins, it has been proposed that the mutations in BRM cause GOF or dominant-negative effects. Hence, these mutations possibly interfere with the ability of ATP hydrolysis by native BRM protein (Van Houdt et al, 2012 ; Ejaz et al, 2016 ). In addition to BRM , missense mutations in BAF47 (p.Arg366Cys) was also reported to present with NCBRS (Wieczorek et al, 2013 ).…”

Section: Role Of Baf Complex In Neurodevelopmental Disordersmentioning

confidence: 99%

Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders

Sokpor

Xie

Rosenbusch

et al. 2017

Front. Mol. Neurosci.

191

170

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The ATP-dependent BRG1/BRM associated factor (BAF) chromatin remodeling complexes are crucial in regulating gene expression by controlling chromatin dynamics. Over the last decade, it has become increasingly clear that during neural development in mammals, distinct ontogenetic stage-specific BAF complexes derived from combinatorial assembly of their subunits are formed in neural progenitors and post-mitotic neural cells. Proper functioning of the BAF complexes plays critical roles in neural development, including the establishment and maintenance of neural fates and functionality. Indeed, recent human exome sequencing and genome-wide association studies have revealed that mutations in BAF complex subunits are linked to neurodevelopmental disorders such as Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, Kleefstra's syndrome spectrum, Hirschsprung's disease, autism spectrum disorder, and schizophrenia. In this review, we focus on the latest insights into the functions of BAF complexes during neural development and the plausible mechanistic basis of how mutations in known BAF subunits are associated with certain neurodevelopmental disorders.

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“…Patient's mutation in black. Mutations reported first by [Van Houdt et al, ] in green, [Wolff et al, ] in orange, [Sousa and Hennekam, ] in blue, [Bramswig et al, ] in purple, and [Ejaz et al, ] in pink. *Recurrent mutations.…”

Section: Discussionmentioning

confidence: 99%

“…SMARCA2 is located on chromosome 9p24.3 and its longest transcript has 34 exons. Thus far, 62 missense mutations and three in‐frame deletions clustering in the ATPase domains of exons 15–25 of SMARCA2 have been reported in patients with NCBRS [Sousa and Hennekam, ; Bramswig et al, ; Ejaz et al, ] (see Fig. for schematic diagram of SMARCA2 protein and location of mutations).…”

Section: Discussionmentioning

confidence: 99%

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

Tang

Hughes

Lascelles

et al. 2016

American J of Med Genetics Pt A

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We report a de novo SMARCA2 missense mutation discovered on exome sequencing in a patient with myoclonic astatic epilepsy, leading to reassessment and identification of Nicolaides–Baraitser syndrome. This de novo SMARCA2 missense mutation c.3721C>G, p.Gln1241Glu is the only reported mutation on exon 26 outside the ATPase domain of SMARCA2 to be associated with Nicolaides–Baraitser syndrome and adds to chromatin remodeling as a pathway for epileptogenesis. © 2016 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.

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The evolving features of Nicolaides–Baraitser syndrome – a clinical report of a 20‐year follow‐up

Cited by 17 publications

References 9 publications

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

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

Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders

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

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