The ARID1B phenotype: What we have learned so far

Abstract

Evidence is now accumulating from a number of sequencing studies that ARID1B not only appears to be one of the most frequently mutated intellectual disability (ID) genes, but that the range of phenotypes caused by ARID1B mutations seems to be extremely wide. Thus, it is one of the most interesting ID genes identified so far in the exome sequencing era. In this article, we review the literature surrounding ARID1B and attempt to delineate the ARID1B phenotype. The vast majority of published ARID1B patients have been ascertained through studies of Coffin-Siris syndrome (CSS), which leads to bias when documenting the frequencies of phenotypic features. Additional observations of those individuals ascertained through exome sequencing studies helps in delineation of the broader clinical phenotype. We are currently establishing an ARID1B consortium, aimed at collecting ARID1B patients identified through genome-wide sequencing strategies. We hope that this endeavor will eventually lead to a more comprehensive view of the ARID1B phenotype.

Coffin-Siris syndrome with café-au-lait spots, obesity and hyperinsulinism caused by a mutation in the <i>ARID1B</i> gene

“…Other findings, present in a smaller subgroup of CSS patients are determined to have small 5th finger or toe nails, short fifth finger, feeding difficulties, agenesis of the corpus callosum, seizures, myopia, and growth delay in the same study (7).…”

The role of objective facial analysis using FDNA in making diagnoses following whole exome analysis. Report of two patients with mutations in the BAF complex genes

“…Phenotypic variability of Coffin-Siris syndrome was recognized prior to identification of its genetic heterogeneity [Schrier Vergano and Deardorff, 2014]. Similarly, significant phenotypic variability has been reported in individuals with intellectual disability due to an ARID1B mutation [Santen et al, 2013[Santen et al, , 2014. Further, phenotypes associated with mutations in ARID1B and multiple other genes encoding components of the BAF complex show significant overlap (Table II) Kosho et al, 2014;Miyake et al, 2014;Bramswig et al, 2015].…”

“…2 in Shain et al, 2015]. Recognizing the dual role of the BAF complex in malignancies and intellectual disabilities, the concern for an increased malignancy risk has previously been considered [Santen et al, 2012[Santen et al, , 2014. No increased malignancy risk has been noted in patients with truncating ARID1B mutations, despite such mutations occurring somatically in malignancies [Santen et al, 2012[Santen et al, , 2014.…”

<i>ARID1B</i>-mediated disorders: Mutations and possible mechanisms

“…In addition, mutations in ARID1B leading to haploinsufficiency were later identified in CoffinSiris syndrome (CSS), which is characterized by ID, severe speech impairment, coarse facial features, microcephaly, developmental delay, and hypoplastic nails of the fifth digits (MIM 135900) (12)(13)(14). Mutations in other genes within the BAF complex have also been found to cause CSS, but ARID1B mutations account for approximately 70% of cases (15). In 2014, the phenotypic spectrum of CSS was further broadened when an individual with CSS with a de novo frameshift mutation in ARID1B presented with extreme obesity, macrocephaly, hepatomegaly, hyperinsulinism, and polycystic ovarian syndrome (16).…”

“…A recent review identified the major features associated with ARID1B haploinsufficiency to be ID, speech delay, coarse facies, and hypertrichosis. Minor features, present in a smaller but significant proportion of individuals, included finger/toe abnormalities, feeding difficulties, agenesis of the corpus callosum, seizures, myopia, and growth delay (15). However, the data were primarily from individuals with a prior clinical diagnosis of CSS and therefore there is likely to be significant ascertainment bias.…”