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

Abstract

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.

Phenotypic expansion of KMT2D‐related disorder: Beyond Kabuki syndrome

“…The characteristics of SWI/SNF‐related intellectual disability disorders, also known as Coffin–Siris spectrum disorders, include some overlap with our patients, including hypertrichosis, thick eyebrows, coarse facial features, and feeding problems (Bogershausen & Wollnik, ), although other facial characteristics of our patients are distinct. Some cases also have bronchopulmonary disease, like our patients.…”

Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay

“…Pathogenic variants reported in SMARC subunits (SMARCA2, SMARCA4, SMARCB1, and SMARCE1) are mostly missense and in-frame deletions ( Table 2) with dominant-negative effect mechanism causing Coffin-Siris and CS-like syndromes. 8,25 Recently, mutations identified in BAF-subunit DPF2 were suggested to cause CSS-like phenotype in a dominant-negative mechanism related both to missense and splicing/truncating variants through NMD escape. 17 Given that SMARCC1 and SMARCC2 are paralogous genes, that they can form heterodimers or homodimers, 70 and that both share functional scaffolding properties, 28 it is conceivable that SMARCC1 could at least partially compensate for the loss of SMARCC2 leading to a milder phenotype in case subjects with truncating mutations in the SMARCC N-terminal region.…”

“…24 Detailed phenotypic and genetic comparison between the different BAF-related syndromes has been discussed elsewhere. 4,25 SMARCC2 (MIM: 601734) encodes BAF170, a common core subunit of the BAF complexes with high homology to SMARCC1 (BAF155). 26 It is an intrinsic factor of glial radial cells and plays a crucial role in embryogenesis and corticogenesis, determining the mammalian body and cortical size.…”

Identification of SMARCD1 as a syndromic intellectual disability gene that is required for memory and context-dependent regulation of neuronal genes in Drosophila

“…Notably, missense mutations are quite common in other SWI/SNF related disorders. While nonsense mutations are common in some SWI/SNF genes (ARID1A, ARID1B, and ARID2), SMARCA4, SMARCA2, SMARCB1, and SMARCE1 are primarily affected by missense mutations with a predicted dominant negative effect 62 .…”