Using NGS we showed that ARID1B at 6q25.3 was truncated in a patient carrying a de novo balanced translocation t(1;6)(p31.1;q25.3). The patient had ACC, intellectual disability, speech impairment, ASD, and mild dysmorphic features. To delineate the clinical features associated with haploinsufficiency of ARID1B, we compared the translocation patient to seven patients with overlapping interstitial de novo deletions.
We included all available patients in this study. Three patients had deletions that only affected ARID1B
. Four patients had larger deletions encompassing 5–73 RefSeq genes, thus haploinsufficiency of other genes is likely to impact the observed phenotypes. Brain MRI was not performed on three of the reported patients; as this procedure would require general anesthesia it was decided against for ethical reasons. Despite these obvious limitations, overlapping clinical manifestations were present: all eight patients had intellectual disability, severe speech impairment, and various degrees of dysmorphic features. Callosal abnormalities were present in four of the five patients where brain imaging was performed. Three patients were diagnosed with ASD and another two showed autistic traits. This is in accordance with two recently published reports describing (i) a small de novo
deletion within ARID1B
in a patient with autism (15
) and (ii) a patient with ACC, intellectual disability, speech impairment, and autism, in which a de novo
translocation disrupted two genes: ARID1B
). Patient 4 had normal brain MRI; this is not surprising as ACC associated loci are known to exhibit reduced penetrance (8
). Interestingly, that same patient had intellectual disability, speech impairment, and ASD, suggesting that these traits might not be associated with visible structural brain abnormalities.
is disrupted by the translocation in patient 1, the expression of the gene could be expected to be halved unless compensatory expression was done from the normal chromosome. The observed expression pattern for primer sets downstream of or spanning the translocation was in concordance with these expectations. As data sets for exons 5–7 and 7–8 exhibit virtually identical relative expression levels, it can be indirectly inferred that the downstream fragment carrying ARID1B
, translocated onto the derivative chromosome 1, is transcriptionally inactive as would be expected because this fragment carries no promoter region. The expressional pattern of exons located upstream of the translocation (exons 4–5) indicates that ARID1B
is expressed at levels higher than for amplicons downstream of the translocation. This indicates that ARID1B
is not only transcriptionally active on the normal chromosome but also from the fragment on der(6) which contains the intact promoter region. It is thus anticipated that the ARID1B
fragment on der(1) is involved in the transcription of a chimeric mRNA consisting of the first five exons of ARID1B
and an unknown part of chromosome 1. Interestingly these data are in concordance with previously published data from Backx et al. (16
) who showed that a fusion transcript between ARID1B
was upregulated twofold in a patient with t(6;14) and a similar phenotype. The reason for the upregulation of ARID1B
on der(6) can only be speculated, but a TargetscanS analysis (UCSC Genome Browser http://genome.ucsc.edu/
) showed the presence of multiple putative miRNA regulatory sites in the 3′ untranslated region of ARID1B
. The lack of these miRNA regulatory sites on der(6) could easily be thought to loosen the expressional control of ARID1B
potentially exerted by these putative regulatory sites, thus leading to increased expression from this allele. More work to confirm this theory, however, is needed.
Our findings emphasize that ARID1B
is important for normal human brain development and function. ARID1B
is a highly conserved gene which furthermore is associated with an evolutionary conserved stable gene desert, a hall mark of key developmental genes (18
). It encodes a DNA-binding protein, ARID1B, that is part of the chromatin-remodeling complex SWI/SNF (19
). Chromatin-remodeling complexes are involved in gene expression regulation. They act by altering the nucleosome structure which leads to changes in the chromatin structure that allows binding of transcriptional factors. Arid1b
is expressed in the developing mouse brain (16
) and studies of mouse embryonic stem cells have found Arid1b (BAF250b) to be particularly important in early development. Levels of BAF250b complexes were found to be high in undifferentiated mouse embryonic stem cells and lower during embryonic stem cell differentiation. Furthermore, BAF250b-deficient mouse embryonic stem cells were less capable of self-renewal and showed increased levels of differentiation (20
). Additional functional studies including a systematic search for ARID1B
target genes may show how haploinsufficiency of ARID1B
predispose to CC defects and to an array of cognitive defects, including severe speech defects.