Genotype-Phenotype Correlations in 208 Individuals with Coffin-Siris Syndrome

Abstract

Coffin-Siris syndrome (CSS, MIM 135900) is a multi-system intellectual disability syndrome characterized by classic dysmorphic features, developmental delays, and organ system anomalies. Genes in the BRG1(BRM)-associated factors (BAF, Brahma associated factor) complex have been shown to be causative, including ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, and SOX4. In order to describe more robust genotype-phenotype correlations, we collected data from 208 individuals from the CSS/BAF complex registry with pathogenic variants in seven of these genes. Data were organized into cohorts by affected gene, comparing genotype groups across a number of binary and quantitative phenotypes. We determined that, while numerous phenotypes are seen in individuals with variants in the BAF complex, hypotonia, hypertrichosis, sparse scalp hair, and hypoplasia of the distal phalanx are still some of the most common features. It has been previously proposed that individuals with ARID-related variants are thought to have more learning and developmental struggles, and individuals with SMARC-related variants, while they also have developmental delay, tend to have more severe organ-related complications. SOX-related variants also have developmental differences and organ-related complications but are most associated with neurodevelopmental differences. While these generalizations still overall hold true, we have found that all individuals with BAF-related conditions are at risk of many aspects of the phenotype, and management and surveillance should be broad.

ARID2, a Rare Cause of Coffin–Siris Syndrome: A Clinical Description of Two Cases

“…ARID1B gene are the most frequently mutated in CSS. The severity of physical abnormalities and intellectual defects varies from person to person (9)(10)(11)(12). We described two other patients with ARID2 gene variation, which is the rarest mutated in CSS.…”

“…It plays an important role in cell proliferation, differentiation, development, and tumor suppression. ATP-dependent chromatin remodeling is a widely used mechanism (12,13). In mammals, 29 genes are predicted to encode protein complexes similar to yeast SWI2/SNF2.…”

Identification of de novo mutations for ARID1B haploinsufficiency associated with Coffin–Siris syndrome 1 in three Chinese families via array-CGH and whole exome sequencing

“…This multi-protein complex contains more than 15 subunits to activate gene expression through its capacity to remodel and remove nucleosomes at gene promoters [ 32 ]. Recently, mutations, translocations and deletions of the subunits in the SWI/SNF complex have been linked to a number of human diseases, such as cancer [ 33 ], different types of CSS [ 4 , 34 – 38 ] and NCBRS [ 15 ].

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Rare Hereditary Gynecological Cancer Syndromes

“…Some studies have reported that germline variants in SMARCB1 and SMARCA4 were involved in the CSS phenotype [137,138]. Germline PVs of SMARCB1 (n = 14, 7%) and SMARCA4 (n = 32, 15%) were also reported to be identified among 208 CSS patients [139].…”