Coffin-Siris Syndrome and the BAF Complex: Genotype-Phenotype Study in 63 Patients

Abstract

De novo germline variants in several components of the SWI/SNF-like BAF complex can cause Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. We screened 63 patients with a clinical diagnosis of CSS for these genes (ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1) and identified pathogenic variants in 45 (71%) patients. We found a high proportion of variants in ARID1B (68%). All four pathogenic variants in ARID1A appeared to be mosaic. By using all variants from the Exome Variant Server as test data, we were able to classify variants in ARID1A, ARID1B, and SMARCB1 reliably as being pathogenic or nonpathogenic. For SMARCA2, SMARCA4, and SMARCE1 several variants in the EVS remained unclassified, underlining the importance of parental testing. We have entered all variant and clinical information in LOVD-powered databases to facilitate further genotype-phenotype correlations, as these will become increasingly important because of the uptake of targeted and untargeted next generation sequencing in diagnostics. The emerging phenotype-genotype correlation is that SMARCB1 patients have the most marked physical phenotype and severe cognitive and growth delay. The variability in phenotype seems most marked in ARID1A and ARID1B patients. Distal limbs anomalies are most marked in ARID1A patients and least in SMARCB1 patients. Numbers are small however, and larger series are needed to confirm this correlation.

Coffin–Siris Syndrome with obesity, macrocephaly, hepatomegaly and hyperinsulinism caused by a mutation in the ARID1B gene

“…Among the patients with ARID1B mutation, the phalangeal changes may or may not exist. 4,9 In our overview, 51/79 (73%) had this finding including our case. Hypertrichosis was described in 94% of patients.…”

“…They are present in at least half of the patients with CSS. 4,7,9 Recently, Wieczorek et al 7 added another causative factor for CSS -the PHF6 gene. Now, at least 87 patients with mutation, deletion, duplication or translocation affecting ARID1B (or BAF250B) have been described.…”

“…[4][5][6][7][9][10][11][12][13][14] Most of them had a clinical diagnosis of CSS, but it can be due to careful clinical preselection for molecular study. [4][5][6][7]9 In some patients, the mutation in ARID1B was found when searching the cause of unexplained intellectual disability (ID) without CSS diagnosis. 11,12 In this study, we report a novel ARID1B mutation identified by whole-exome sequencing in a patient with clinical features characteristic to CSS.…”

De novo SOX11 mutations cause Coffin–Siris syndrome

“…1). Five subunit genes (SMARCB1, SMARCA4, SMARCE1, ARID1A and ARID1B) of the BAF complex (also known in yeast as the SWI/SNF complex 1 ) are mutated in 55-70% of CSS patients [2][3][4][5][6] . Mutations in SMARCA2, another BAF complex gene, were reported in the Nicolaides-Baraitser syndrome, which is similar to, but distinct from CSS 7 .…”

“…Furthermore, de novo PHF6 mutations were found in two CSS patients 6 , although no direct interaction has been reported between the BAF complex and PHF6, which interacts with the nucleosome remodelling and deacetylation complex 6 . As 30-45% of CSS patients were genetically undiagnosed in three large cohort studies [2][3][4][5][6] , further genetic investigation is required to fully address the genetic picture of CSS.…”