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.
Highlights
The SWI/SNF complex, first purified and characterized in yeast, is one of a group of ATP-dependent chromatin remodeling complexes, which regulate DNA accessibility at the nucleosome by mobilizing nucleosomes in an ATP-dependent manner (Kassabov et al, 2003; Zofall et al, 2006)
Since the SWI/SNF complex is of prime clinical importance both in human genetics as well as in oncology, vivid, and elaborate research is being conducted worldwide in order to unravel the cellular and developmental effects of altered chromatin regulation, and to understand the pathogenesis of SWI/SNF related disorders
The details of the functional research conducted so far are beyond the scope of this review, which is focused on the clinical and molecular genetic aspects of SWI/SNFrelated intellectual disability disorders” (SSRIDDs)
Summary
The SWI/SNF (switch/sucrose non-fermenting) complex, first purified and characterized in yeast, is one of a group of ATP-dependent chromatin remodeling complexes, which regulate DNA accessibility at the nucleosome by mobilizing nucleosomes in an ATP-dependent manner (Kassabov et al, 2003; Zofall et al, 2006). We would like to modify the suggestion made by Santen et al (2012) and propose that in addition to patients with an obvious CSS phenotype, a diagnosis of ARID1B-related SSRIDD should be considered in every patient with unexplained ID and speech impairment, especially if ACC and/or a coarse facial appearance are perceived (Table 1). This approach will certainly increase the diagnostic yield compared to a more broadly defined indication. Facial asymmetry is obvious in two patients with mutations in ARID1A depicted in Kosho et al (2014) and may, if present, be an additional clue to diagnosis (Table 1)
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