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

TLDR

Corpus callosum abnormalities, ranging from severe intellectual disability to normal cognition, are common brain malformations that are often genetic, yet the underlying causes remain largely unknown. Next‑generation mate‑pair sequencing mapped chromosomal breakpoints in a patient with a de‑novo balanced t(1;6)(p31;q25) translocation, revealing a truncation of ARID1B. Truncation of ARID1B in this patient, coupled with altered expression and comparison to other ARID1B‑deletion cases, confirms that ARID1B haploinsufficiency causes corpus callosum abnormalities, intellectual disability, severe speech impairment, and autism, underscoring its role in brain development.

Abstract

Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. 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 Phenotype-genotype comparison of the translocation patient to seven unpublished patients with various sized deletions encompassing ARID1B confirms that haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual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.