Switch/Sucrose Non-Fermentable (SWI/SNF)-related intellectual disability disorders (SSRIDDs) and Cornelia de Lange syndrome are rare syndromic neurodevelopmental disorders with overlapping clinical phenotypes. SSRIDDs are associated with the BAF (Brahma-Related Gene-1 Associated Factor) complex, whereas CdLS is a disorder of chromatin modification associated with the cohesin complex. Here, we used RNA interference in Drosophila melanogaster to reduce expression of six genes (brm, osa, Snr1, SMC1, SMC3, vtd) orthologous to human genes associated with SSRIDDs and CdLS. These fly models exhibit changes in sleep, activity, startle behavior (a proxy for sensorimotor integration) and brain morphology. Whole genome RNA sequencing identified 9,657 differentially expressed genes (FDR < 0.05), 156 of which are differentially expressed in both sexes in SSRIDD- and CdLS-specific analyses, including Bap60, which is orthologous to SMARCD1, a SSRIDD-associated BAF component, k-means clustering reveals genes co-regulated within and across SSRIDD and CdLS fly models. RNAi-mediated reduction of expression of six genes co-regulated with focal genes brm, osa, and/or Snr1 recapitulated changes in behavior of the focal genes. Based on the assumption that fundamental biological processes are evolutionarily conserved, Drosophila models can be used to understand underlying molecular effects of variants in chromatin-modification pathways and may aid in discovery of drugs that ameliorate deleterious phenotypic effects.

As a clinical subtype of SWI/SNF-related intellectual disability syndromes, Nicolaides-Baraitser syndrome (NCBRS, OMIM601358) has a unique genotype-phenotype. Due to the scarcity of the number of cases reported and the limitations of diagnosis methods, so far only more than 80 cases have been reported worldwide. In this article, a new patient with a de novo mutation was followed up for 10 years; it includes the epilepsy treatment process, the characteristics of NBCRS with seizures, typical faces, sparse hair, prominent interphalangeal joints, and intellectual disability, and we also summarized the genotype-phenotype of the 80 reported cases for comparison. Due to insufficient studies and lack of attention paid to the syndrome, it is believed that the actual number of cases should be far more than the reported number. The syndrome is phased and progressive. The genotype-phenotype correlation of the disease is related to the location of the gene locus, especially closely related to the SNF2 ATPase domain. CONCLUSIONS: The understanding of NCBRS is lagging, we need to strengthen the screening process of the phenotypic disease with intellectual disability, and perfecting multiple types of diagnostic techniques will help the discovery of the disease; its clinical features are staged and are slowly progressive, and long-term prognosis must be taken precautious with long-term follow-up required.

Nicolaides-Baraitser syndrome (NCBRS) is a rare disorder characterized by neurodevelopmental delays, seizures, and diverse physical characteristics. The DNA methylation (DNAm) profile in NCBRS is significantly different. DNAm is linked to the biological aging of cells and the health risks associated with biological aging. In this study, we examined changes in biological ages in NCBRS to provide insights into the prognosis and health risks of NCBRS.
We used a publicly available dataset to examine biological aging in NCBRS using DNAm-based epigenetic ages, such as PhenoAge and GrimAge, as well as DNAm-based estimator of telomere length (DNAmTL). We investigated 12 cases, clinically diagnosed as NCBRS, and 27 controls.
Compared to controls, NCBRS cases exhibited significantly accelerated PhenoAge and GrimAge as well as significantly shortened DNAmTL.
These results suggest an acceleration of biological aging in NCBRS and provide insights into the prognosis and health risks of NCBRS.

BACKGROUND: Nicolaides-Baraitser syndrome (NCBRS) is a severe neurodevelopmental disorder with multiple abnormalities. To date, all pathogenic variants in SMARCA2 causing NCBRS are de novo and most are missense variants located in the ATPase domain of SMARCA2 protein.
METHODS: In this study, a familial trio whole-exome sequencing was performed on the proband presenting with intellectual disability, early-onset epilepsy, and autistic features. A novel missense variant c.553C>G (p.Gln185Glu) in SMARCA2 was identified, which is located in the QLQ domain. The same variant was subsequently also found in the mother\'s ongoing pregnancy. Samples from accessible tissues such as saliva and sperm other than blood were collected from the parents, and the detection of the target variant was performed by amplicon-based deep sequencing.
RESULTS: Low-level mosaicism of the target variant c.553C>G (p.Gln185Glu) was detected in the father\'s sperm with allele fraction of 2.8% by amplicon-based deep sequencing, which was not detected in either parents\' blood or saliva specimens. Heterozygosity of this variant was confirmed in the proband.
CONCLUSIONS: This is the first report of paternal germline mosaicism for a SMARCA2 disease-causing variant. In addition, the missense variant c.553C>G (p.Gln185Glu) in the QLQ domain causes mainly neurological and developmental phenotypes with unremarkable characteristic facial features and limb abnormalities. Our findings expand the phenotypic spectrum and mode of genetic transmission associated with the SMARCA2 variants.

Nicolaides-Baraitser syndrome (NCBRS) is a rare disease caused by mutations in the SMRCA2 gene, which affects chromatin remodelling and leads to a wide range of symptoms including microcephaly, distinct facial features, recurrent seizures, and severe mental retardation. Until now, less than 100 cases have been reported.
A 22-month old male infant with NCBRS underwent elective cleft palate surgery. The anaesthetists were challenged by the physiological condition of the patient: narrow face, very small mouth, mild tachypnea, slight sternal retractions, physical signs of partial monosomy 9p, and plagiocephalus, midface hypoplasia, V-shaped cleft palate, enhanced muscular hypotension, dysplastic kidneys (bilateral, estimated GFR: approx. 40 ml/m2), nocturnal oxygen demand, and combined apnea. In addition, little information was available about interaction of the NCBRS displayed by the patient and anaesthesia medications.
The cleft palate was successfully closed using the bridge flap technique. Overall, we recommend to perform a trial video assisted laryngoscopy in the setting of spontaneous breathing with deep inhalative anaesthesia before administration of muscle relaxation to detect any airway difficulties while remaining spontaneoues breathing and protective reflexes.

Nicolaides-Baraitser syndrome (NCBRS) is a rare congenital genetic disorder characterized by distinctive facial features similar to Treacher Collins syndrome (TCS). We report the first case of successful nasal fiberoptic intubation in a patient with NCBRS with micrognathia and limited mouth opening due to trismus. A 9-year-old girl with NCBRS and dental caries was scheduled to undergo general anesthesia for a dental extraction. Initial attempts at oral intubation using a video laryngoscope were unsuccessful. However, subsequent attempts at nasal intubation using a flexible fiberoptic scope were successful. This report highlights that patients with NCBRS may present with difficult airways to manage and intubate.

ARID2 loss-of-function is associated with a rare genetic disorder characterized in 14 reported patients to date. ARID2 encodes a member of the SWItch/sucrose non-fermentable chromatin remodeling complex. Other genes encoding subunits of this complex, such as ARID1A, ARID1B, and SMARCA2, are mutated in association with Coffin-Siris syndrome (CSS) and Nicolaides Baraitser syndrome (NCBRS) phenotypes. Previously reported ARID2 mutations manifested clinically with a CSS-like phenotype including intellectual disability, coarsened facial features, fifth toenail hypoplasia, and other recognizable dysmorphisms. However, heterogeneity exists between previously reported patients with some patients showing more overlapping features with NCBRS. Herein, we present a patient with a novel disease-causing ARID2 loss-of-function mutation. His clinical features included intellectual disability, coarse and dysmorphic facial features, toenail hypoplasia, ADHD, short stature, and delayed development consistent with prior reports. Our patient also presented with previously unreported clinical findings including ophthalmologic involvement, persistent fetal fingertip and toetip pads, and diffuse hyperpigmentary and hypopigmentary changes sparing his face, palms, and soles. The anomalous skin findings are particularly of interest given prior literature outlining the role of ARID2 in melanocyte homeostasis and melanoma. This clinical report and review of the literature is further affirming of the characteristic symptoms and expands the phenotype of this newly described and rare syndrome.

Mutations in genes that encode proteins of the SWI/SNF complex, called BAF complex in mammals, cause a spectrum of disorders that ranges from syndromic intellectual disability to Coffin-Siris syndrome (CSS) to Nicolaides-Baraitser syndrome (NCBRS). While NCBRS is known to be a recognizable and restricted phenotype, caused by missense mutations in SMARCA2, the term CSS has been used lately for a more heterogeneous group of phenotypes that are caused by mutations in either of the genes ARID1B, ARID1A, ARID2, SMARCA4, SMARCB1, SMARCE1, SOX11, or DPF2. In this review, we summarize the current knowledge on the phenotypic traits and molecular causes of the above named conditions, consider the question whether a clinical distinction of the phenotypes is still adequate, and suggest the term \"SWI/SNF-related intellectual disability disorders\" (SSRIDDs). We will also outline important features to identify the ARID1B-related phenotype in the absence of classic CSS features, and discuss distinctive and overlapping features of the SSRIDD subtypes. Moreover, we will briefly review the function of the SWI/SNF complex in development and describe the mutational landscapes of the genes involved in SSRIDD.

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.

Coffin-Siris syndrome is a rare congenital malformation and intellectual disability syndrome. Mutations in at least seven genes have been identified. Here, we performed copy number analysis in 37 patients with features of CSS in whom no causative mutations were identified by exome sequencing. We identified a patient with a 9p24.3-p22.2 duplication and another patient with the chromosome der(6)t(6;9)(p25;p21)mat. Both patients share a duplicated 15.8-Mb region containing 46 protein coding genes, including SMARCA2. Dominant negative effects of SMARCA2 mutations may contribute to Nicolaides-Baraitser syndrome. We conclude that their features better resemble Coffin-Siris syndrome, rather than Nicolaides-Baraitser syndrome and that these features likely arise from SMARCA2 over-dosage. Pure 9p duplications (not caused by unbalanced translocations) are rare. Copy number analysis in patients with features that overlap with Coffin-Siris syndrome is recommended to further determine their genetic aspects. © 2016 Wiley Periodicals, Inc.