Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B

Abstract

Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe intellectual disability to normal cognitive function. The etiology is expected to be genetic in as much as 30–50% of the cases, but the underlying genetic cause remains unknown in the majority of cases. By next-generation mate-pair sequencing we mapped the chromosomal breakpoints of a patient with a de novo balanced translocation, t(1;6)(p31;q25), agenesis of corpus callosum (CC), intellectual disability, severe speech impairment, and autism. The chromosome 6 breakpoint truncated ARID1B which was also truncated in a recently published translocation patient with a similar phenotype. Quantitative polymerase chain reaction (Q-PCR) data showed that a primer set proximal to the translocation showed increased expression of ARID1B, whereas primer sets spanning or distal to the translocation showed decreased expression in the patient relative to a non-related control set. Phenotype–genotype comparison of the translocation patient to seven unpublished patients with various sized deletions encompassing ARID1B confirms that haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual disability, severe speech impairment, and autism. Our findings emphasize that ARID1B is important in human brain development and function in general, and in the development of CC and in speech development in particular.

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

“…Our case has no fifth digit involvement similar to some earlier CSS cases with ARID1B mutations (3,8,9). Although microcephaly has been mentioned as a feature of CSS (10), we did not observe it in our patient compared to some larger CSS cohort studies (11).…”

Array‐based molecular karyotyping in fetal brain malformations: Identification of novel candidate genes and chromosomal regions

“…ARID1B causes Coffin Siris syndrome (Santen et al, 2012), a syndrome associated with ACC. De novo intragenic deletions of ARID1B have been reported in individuals with either ACC or autism (Backx et al, 2011;Halgren et al, 2012) suggesting ARID1B a likely candidate gene for ACC.…”

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

“…[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.…”