Coffin–Siris syndrome is a SWI/SNF complex disorder

Abstract

Coffin-Siris syndrome (CSS) is a congenital disorder characterized by intellectual disability, growth deficiency, microcephaly, coarse facial features, and hypoplastic or absent fifth fingernails and/or toenails. We previously reported that five genes are mutated in CSS, all of which encode subunits of the switch/sucrose non-fermenting (SWI/SNF) ATP-dependent chromatin-remodeling complex: SMARCB1, SMARCA4, SMARCE1, ARID1A, and ARID1B. In this study, we examined 49 newly recruited CSS-suspected patients, and re-examined three patients who did not show any mutations (using high-resolution melting analysis) in the previous study, by whole-exome sequencing or targeted resequencing. We found that SMARCB1, SMARCA4, or ARID1B were mutated in 20 patients. By examining available parental samples, we ascertained that 17 occurred de novo. All mutations in SMARCB1 and SMARCA4 were non-truncating (missense or in-frame deletion) whereas those in ARID1B were all truncating (nonsense or frameshift deletion/insertion) in this study as in our previous study. Our data further support that CSS is a SWI/SNF complex disorder.

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.…”

“…8 So far, only nonsense and frameshift mutations in ARID1B as well as whole-gene deletions have been identified in patients with CSS. [4][5][6]12 In our patient, a 1-bp deletion c.1584delG in ARID1B predicted to cause a frameshift and a premature termination of the protein p.(Leu528Phefs*65) was identified. This alteration most likely results in loss-of-function of the protein, suggesting haploinsufficiency as a disease-causing mechanism.…”

“…1,2 Also, other ectodermal, constitutional and/or organ-related features may be present. 3 CSS is now classified as a BAF (also known as SWI/SNF) complex disorder, 4 as several syndrome-related genes that encode subunits of the BAF complex -ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCA2 and SMARCE1 -have been identified. [5][6][7] The BAF complex modulates chromatin structure and has important roles in transcription, cell differentiation, DNA repair and tumor suppression as reviewed by Hargreaves and Crabtree.…”

“…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.…”