Haploinsufficiency of ARID1B, a Member of the SWI/SNF-A Chromatin-Remodeling Complex, Is a Frequent Cause of Intellectual Disability

Abstract

Intellectual disability (ID) is a clinically and genetically heterogeneous common condition that remains etiologically unresolved in the majority of cases. Although several hundred diseased genes have been identified in X-linked, autosomal-recessive, or syndromic types of ID, the establishment of an etiological basis remains a difficult task in unspecific, sporadic cases. Just recently, de novo mutations in SYNGAP1, STXBP1, MEF2C, and GRIN2B were reported as relatively common causes of ID in such individuals. On the basis of a patient with severe ID and a 2.5 Mb microdeletion including ARID1B in chromosomal region 6q25, we performed mutational analysis in 887 unselected patients with unexplained ID. In this cohort, we found eight (0.9%) additional de novo nonsense or frameshift mutations predicted to cause haploinsufficiency. Our findings indicate that haploinsufficiency of ARID1B, a member of the SWI/SNF-A chromatin-remodeling complex, is a common cause of ID, and they add to the growing evidence that chromatin-remodeling defects are an important contributor to neurodevelopmental disorders.

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

“…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.…”

“…To compare the clinical characteristics between the patients, we give an overview of all previously described patients with mutation in the ARID1B gene in addition to our patient (Supplementary Table 2). So far, all described patients with ARID1B changes have HC within normal limits or demonstrated microcephaly, except for one patient in Hoyer et al 12 and one in Wieczorek et al 7 group. Our patient has significant macrocephaly ( þ 5 SD) and Arnold-Chiari malformation type I.…”

“…[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.…”

“…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.…”

BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems

“…Dias et al (2016) showed differential expression of BAF swi/snf related genes in the hippocampus of Bcl11a haploinsufficient mice, suggesting that BCL11A is a BAFopathy gene. In this context, it is noticeable that, before performing research exome sequencing, the unique gene we selected for clinical Sanger sequencing, based on dysmorphology criteria present in our patient, was ARID1B , a classic BAFopathy gene (Hoyer et al, 2012). …”