Nicolaides-Baraitser Syndrome Research Articles

Generation of an induced pluripotent stem cell (iPSC) line SDQLCHi056-A from a patient with Nicolaides-Baraitser syndrome carrying a mutation in SMARCA2 gene

Nicolaides-Baraitser syndrome (NCBRS) is characterized by severe mental retardation, early-onset seizures, short stature, dysmorphic facial features, and sparse hair. Heterozygous mutations in the SMARCA2 gene are the most common cause of NCBRS. Here, we generated an induced pluripotent stem cell line SDQLCHi056-A from a five-year-old girl with NCBRS caused by heterozygous mutation (c.3592 G > A, p.V1198M) in the SMARCA2 gene (OMIM#601358). The established iPSC line was validated by pluripotency markers, original gene mutation and demonstrated trilineage differentiation potential in vitro.

Autism spectrum disorder in a patient with Nicolaides-Baraitser Syndrome: case report

Autism spectrum disorder in a patient with Nicolaides-Baraitser Syndrome: case report

Analysis of clinical characteristics and genetic variant in a child with Nicolaides-Baraitser syndrome due to maternal mosaicism

To carry out genetic testing for a child featuring global developmental delay, abnormal liver function, congenital heart disease, and brain malformation. Peripheral blood samples of the child and his parents were collected for the extraction of genomic DNA and trio-whole exome sequencing. Candidate variant was verified by Sanger sequencing. Genetic testing revealed that the child has harbored a heterozygous c.2002G>T (p.Glu668Ter) variant of the SMARCA2 gene, which was predicted to be likely pathogenic by bioinformatic analysis. His mother was found to be a low-percentage mosaic for the same variant, with a ratio of 0.054 (246/4549). The child was diagnosed with Nicolaides-Baraitser syndrome resulting from maternal mosaicism for the SMARCA2 gene variant.

Ten‐year follow‐up of Nicolaides–Baraitser syndrome with a de novo mutation and analysis of 58 gene loci of SMARCA2‐associated NCBRS

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.ConclusionsThe 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.

EP159: A TOPBP1 variant associated With BAFopathy methylation pattern

DNA Topoisomerase II Binding Protein 1 (TOPBP1) is a topoisomerase involved in maintaining genomic integrity via numerous functions including the regulation of DNA replication and replication stress response. A number of studies have shown that TOPBP1 also interacts with the BAF complex. The BAF complex is a group of ATP-dependent chromatin remodeling enzymes, including 10-12 proteins that regulate the nucleosomal structure by altering histone-DNA interactions. For example, the BRCT motif of TOPBP1 interacts with E2F1, a transcription factor, by recruiting BRG1/BRM, a core member of the BAF complex, to prevent apoptosis. In addition, TOPBP1 directly associates with BRG1(SMARCA4) and BAF250a (ARID1A) in the BAF complex to prevent DNA entanglement during mitosis. While TOPBP1 is not currently associated with a genetic syndrome, the BAF complex proteins with which it interacts are associated with BAFopathies such as Coffin Siris Syndrome (CSS) and Nicolaides-Baraitser Syndrome (NCBRS). For example, the gene encoding BRG1 (SMARCA4) is mutated in 11% of individuals affected by CSS, and the gene encoding BRM (SMARCA2) is mutated in almost all NCBRS patients. The gene encoding BAF250a (ARID1A) is also associated with CSS. We have previously demonstrated overlapping DNA methylation episignatures in individuals with CSS and NCBRS, consistent with a common functional basis of these disorders. A 15-month-old boy, born to first cousin Syrian parents, presented with respiratory distress, recurrent aspiration pneumonia, failure to thrive, seizure disorder, cortical blindness, microcephaly, and severe developmental delay. He was born at term weighing 2.2 kg and started having seizures at 4 months. At 8 months, after his first aspiration pneumonia, he stopped sucking and swallowing. At 15 months, he was very small with weight, length, and head circumference at a 4 to 8 month level. He made few attempts to move spontaneously and had no head control. He did not fix or follow, showed no blinking response to threat, and had disconjugate and roving eye movements. There was no response to sounds. He had a right plagiocephaly, deficiency of the lateral eyebrows, high arched palate, and long ears. No organomegaly was noted. He had significant central hypotonia with head lag. There was spasticity with flexion contractures in the upper extremities. Lower extremities had normal tone with hyperreflexia. He had intermittent spontaneous hip flexion. Family history was positive for a sister who developed seizures at 8 months, had poor vision and developmental delay, and died at 7 years. A brother has mild to moderate intellectual delay with no history of seizures or poor vision. MRI of the head showed severe cerebral atrophy with nonobstructive hydrocephalus ex-vacuo. An echocardiogram showed moderate aortic root dilatation. Metabolic testing was negative. Chromosome microarray was normal. Exome sequencing with trio analysis showed a de novo variant of uncertain significance in a candidate gene, NM_007027.3(TOPBP1):c.2396C>T, p.(Ala799Val). He was also hemizygous for a maternally inherited VUS in MAP7D2 and heterozygous for a paternally inherited VUS in TGFBR3. DNA from peripheral blood was analyzed by EpiSign version 3 which includes an episignature for BAFopathies based on pathogenic variants in ARID1A, ARID1B, SMARCB1, SMARCA4, and SMARCA2. Results showed a methylation pattern which was inconclusive with mild methylation differences overlapping the episignature for CSS and NCBRS. There is an overlap between this patient’s phenotype and the features of CSS and NCBRS. For example, CSS and NCBRS can present with variable degrees of developmental delay, seizures, feeding difficulties, hypotonia, visual deficits, slow growth, and microcephaly. NCBRS can also present with regression or lack of developmental progress, especially at the onset of seizures, and CSS is associated with frequent upper respiratory tract infections. In this patient with a VUS in TOPBP1, the overlap of methylation profile with CSS and NCBRS is intriguing, given the known interaction of TOPBP1 with the BAF complex. We propose that the child’s clinical features and methylation findings may be due to a disruption of the TOPBP1-BAF interaction and that the TOPBP1 variant is actually pathogenic. Since there is currently no known association between TOPBP1 and any genetic syndrome, we suggest that any cases with TOPBP1 variants identified through exome sequencing be assessed for the episignature associated with the BAFopathies.

Accelerated epigenetic age and shortened telomere length based on DNA methylation in Nicolaides-Baraitser syndrome.

BackgroundNicolaides–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.MethodsWe 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.ResultsCompared to controls, NCBRS cases exhibited significantly accelerated PhenoAge and GrimAge as well as significantly shortened DNAmTL.ConclusionThese results suggest an acceleration of biological aging in NCBRS and provide insights into the prognosis and health risks of NCBRS.

SWI/SNF-Related SMARCA2 Gene Mutation Associated with Nicolaides-Baraitser's Syndrome: Follow-up Study.

Nicolaides-Baraitser's syndrome is a rare, dominantly inherited well-delineated syndrome caused by mutations in the SMARCA2 gene which is located on the small arm of chromosome 9. In this study, a de novo missense variant, which was identified in a 3-year-old boy by whole exome sequencing is reported. The de novo heterozygous V1198M missense variant in SMARCA2 gene in exon 25 is novel. Identifying the condition is crucial for the long-term management and family counseling. Follow-up over 4 years revealed improvements in overall performance.

Anaesthesia and orphan disease: management of a case of Nicolaides-Baraitser syndrome undergoing cleft palate surgery

BackgroundNicolaides-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.Case presentationA 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.ConclusionsThe 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.

Difficult Airway Management in a Patient With Nicolaides-Baraitser Syndrome Who Had a Small Jaw and Limited Mouth Opening

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.

Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects.

Nicolaides-Baraitser syndrome (NCBRS), caused by a mutation in the SMARCA2 gene, which goes along with intellectual disability, congenital malformations, especially of face and limbs, and often difficult-to-treat epilepsy, is surveyed focusing on epilepsy and its treatment. Patients were recruited via "Network Therapy of Rare Epilepsies (NETRE)" and an international NCBRS parent support group. Inclusion criterion is NCBRS-defining SMARCA2 mutation. Clinical findings including epilepsy classification, anticonvulsive treatment, electroencephalogram (EEG) findings, and neurodevelopmental outcome were collected with an electronic questionnaire. Inclusion of 25 NCBRS patients with epilepsy in 23 of 25. Overall, 85% of the participants (17/20) reported generalized seizures, the semiology varied widely. EEG showed generalized epileptogenic abnormalities in 53% (9/17), cranial magnetic resonance imaging (cMRI) was mainly inconspicuous. The five most frequently used anticonvulsive drugs were valproic acid (VPA [12/20]), levetiracetam (LEV [12/20]), phenobarbital (PB [8/20]), topiramate (TPM [5/20]), and carbamazepine (CBZ [5/20]). LEV (9/12), PB (6/8), TPM (4/5), and VPA (9/12) reduced the seizures' frequency in more than 50%. Temporary freedom of seizures (>6 months) was reached with LEV (4/12), PB (3/8), TPM (1/5, only combined with PB and nitrazepam [NZP]), and VPA (4/12). Seizures aggravation was observed under lamotrigine (LTG [2/4]), LEV (1/12), PB (1/8), and VPA (1/12). Ketogenic diet (KD) and vagal nerve stimulation (VNS) reduced seizures' frequency in one of two each. This first worldwide retrospective analysis of anticonvulsive therapy in NCBRS helps to treat epilepsy in NCBRS that mostly shows only initial response to anticonvulsive therapy, especially with LEV and VPA, but very rarely shows complete freedom of seizures in this, rather genetic than structural epilepsy.

De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides–Baraitser syndrome

PurposeNontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides–Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown. MethodsBy next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes. ResultsOf 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification. ConclusionWe identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

ACGH may be useful in Case of Dominant Disorders Known to be Caused by Gene Mutations: Two Case Reports

We describe two cases where clinical diagnoses were carried out (Rett syndrome-like and Nicolaides-Baraitser syndrome) with no identified mutation respectively in the CDKL5 and the SMARCA2 genes. Conversely a chromosomal microdeletion with contiguous deletion of a part of these two genes was found by arrayCGH in each corresponding case. The aim of this report is then to highlight the possible implication of chromosomal microdeletions with contiguous gene deletions in dominant pathologies where no mutation is found in the causative gene.

Analysis of SMARCA2 gene mutation in a child with Nicolaides-Baraitser syndrome

To explore the molecular basisfor a child featuring short stature, abnormal facial features and developmental delay. Genomic DNA was extracted from peripheral blood samples from the child and his family members. Next-generation sequencing was carried out to screen the whole exomes of the core family. Detected variants were filtered and analyzed according to the standards and guidelines for the interpretation of sequence variants recommended by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Trio-based sequencing has identified a de novo variant c.3593T>G (p.Val1198Gly) in the SMARCA2 gene in the patient. The variant was located in the Helicase C-terminal domain and was classified as pathogenic based on the guidelines. The patient was diagnosed with Nicolaides-Baraitser syndrome caused by SMARCA2 gene mutation.

Heterozygous Mutations in SMARCA2 Reprogram the Enhancer Landscape by Global Retargeting of SMARCA4.

Mammalian SWI/SNF complexes are multi-subunit chromatin remodeling complexes associated with an ATPase (either SMARCA4 or SMARCA2). Heterozygous mutations in the SMARCA2 ATPase cause Nicolaides-Baraitser syndrome (NCBRS), an intellectual disability syndrome associated with delayed speech onset. We engineered human embryonic stem cells (hESCs) to carry NCBRS-associated heterozygous SMARCA2 K755R or R1159Q mutations. While SMARCA2 mutant hESCs were phenotypically normal, differentiation to neural progenitors cells (NPCs) was severely impaired. We find that SMARCA2 mutations cause enhancer reorganization with loss of SOX3-dependent neural enhancers and prominent emergence of astrocyte-specific de novo enhancers. Changes in chromatin accessibility at enhancers were associated with an increase in SMARCA2 binding and retargeting of SMARCA4. We show that the AP-1 family member FRA2 is aberrantly overexpressed in SMARCA2 mutant NPCs, where it functions as a pioneer factor at de novo enhancers. Together, our results demonstrate that SMARCA2 mutations cause impaired differentiation through enhancer reprogramming via inappropriate targeting of SMARCA4.

睡眠時無呼吸, 小顎, 開口制限を伴うニコライデスバライスター症候群患児の全身麻酔経験

睡眠時無呼吸, 小顎, 開口制限を伴うニコライデスバライスター症候群患児の全身麻酔経験

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

BackgroundNicolaides-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.MethodsGenome-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.ResultsWe 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.ConclusionsHere we find that a DNAm signature of SMARCA2 pathogenic variants in NCBRS maps to CpGs relevant to disorder pathophysiology, classifies VUS, and is sensitive to the position of the variant in SMARCA2. The patient with an intermediate model score demonstrating a unique genotype-epigenotype-phenotype correlation underscores the potential utility of this signature as a functionally relevant VUS classification system scalable beyond binary “benign” versus “pathogenic” scoring. This is a novel feature of DNAm signatures that could enable phenotypic predictions from genotype data. Our findings also demonstrate that DNAm signatures can be domain-specific, highlighting the precision with which they can reflect genotypic variation.

Inflammatory Arthritis as a Possible Feature of Coffin-Siris Syndrome

Coffin-Siris syndrome (CSS) and Nicolaides-Baraitser syndrome (NBS) are 2 overlapping syndromes caused by mutations in genes of the barrier-to-autointegration factor chromatin-remodeling complex, presenting with multiple malformations and intellectual disability. Musculoskeletal changes such as noninflammatory prominence of interphalangeal joints in hands, feet, and, to a lesser extent, knee joints are common in NBS (up to 85%) and also reported in CSS. We present the case of a 7-year-old boy with polyarthritis of several years' duration (without uveitis), developmental delay, microcephaly, and dysmorphic features reminiscent of NBS. Sanger sequencing of the SMARCA2 gene revealed no mutations. Laboratory test results were normal. With synovial biopsy, we confirmed a chronic inflammatory synovitis. Brain MRI revealed dysgenesis of the corpus callosum. Treatment with methotrexate and, subsequently, etanercept led to significant clinical improvement. Whole-exome sequencing revealed a de novo heterozygous nonsense mutation in the ARID1B gene, resulting in a premature stop codon (c.C5404T; p.R1802×), a genotype consistent with CSS. The absence of significantly raised inflammatory markers and a clinical diagnosis of a genetic syndrome associated with noninflammatory joint changes may have contributed to this patient's polyarthritis being missed for several years. We propose that some patients with CSS may have inflammatory arthritis (with or without coexisting skeletal dysplasia), which may be helped by treatment as described herein. Early recognition and treatment of inflammatory arthritis in CSS would have a significant impact on reducing disease burden and improving quality of life for patients with this rare genetic syndrome.

A Syndromic Neurodevelopmental Disorder Caused by Mutations in SMARCD1, a Core SWI/SNF Subunit Needed for Context-Dependent Neuronal Gene Regulation in Flies

Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause neurodevelopmental disorders (NDDs). Here, we report on five individuals with mutations in SMARCD1; the individuals present with developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. Trio exome sequencing proved the mutations to be de novo in four of the five individuals. Mutations in other SWI/SNF components cause Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, or other syndromic and non-syndromic NDDs. Although the individuals presented here have dysmorphisms and some clinical overlap with these syndromes, they lack their typical facial dysmorphisms. To gain insight into the function of SMARCD1 in neurons, we investigated the Drosophila ortholog Bap60 in postmitotic memory-forming neurons of the adult Drosophila mushroom body (MB). Targeted knockdown of Bap60 in the MB of adult flies causes defects in long-term memory. Mushroom-body-specific transcriptome analysis revealed that Bap60 is required for context-dependent expression of genes involved in neuron function and development in juvenile flies when synaptic connections are actively being formed in response to experience. Taken together, we identify an NDD caused by SMARCD1 mutations and establish a role for the SMARCD1 ortholog Bap60 in the regulation of neurodevelopmental genes during a critical time window of juvenile adult brain development when neuronal circuits that are required for learning and memory are formed.

Mutational Landscapes and Phenotypic Spectrum of SWI/SNF-Related Intellectual Disability Disorders

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.

Germline variants in SMARCB1 and other members of the BAF chromatin-remodeling complex across human disease entities: a meta-analysis.

Germline variants that affect function are found in seven genes of the BAF chromatin-remodeling complex. They are linked to a broad range of diseases that, according to the gene affected, range from non-syndromic or syndromic neurodevelopmental disorders to low-grade tumors and malignancies. In the current meta-analysis, we evaluate genetic and clinical data from more than 400 families and 577 patients affected by BAF germline alterations. We focus on SMARCB1, including 43 unpublished patients from the EU-RHAB registry and our institution. For this gene, we further demonstrate whole gene as well as exon deletions and truncating variants to be associated with malignancy and early-onset disease. In contrast, non-truncating variants are associated with non-malignant disorders, such as Coffin-Siris syndrome or late-onset tumors like schwannoma or meningioma (p < 0.0001). SMARCB1 germline variants are distributed across the gene with variants in exons 1, 2, 8, and 9 being associated with low-grade entities, and single-nucleotide variants or indels outside of exon 9 that appear in patients with malignancies (p < 0.001). We attribute variants in specific BAF genes to certain disease entities. Finally, single-nucleotide variants and indels are sometimes detected in the healthy relatives of tumor patients, while Coffin-Siris syndrome and Nicolaides-Baraitser syndrome generally seem to appear de novo. Our findings add further information on the genotype-phenotype association of germline variants detected in genes of the BAF complex. Functional studies are urgently needed for a deeper understanding of BAF-related disorders and may take advantage from the comprehensive information gathered in this article.