The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Abstract

PurposePathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting.MethodsClinicians entered clinical data in an extensive web-based survey.Results79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified.ConclusionThere are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.

Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development

“…Specifically, ectopic neurons were found throughout the medulla, inferior olive, and the white matter of the cerebellum 8 . In a recent report of 143 different patients with ARID1B mutations, these original observations about CSS remain consistent, with agenesis or hypoplasia of the corpus callosum prevalent in 43% of patients 9 .…”

“…It was unexpected to find that our Arid1b +/mice did not show motor-independent cognitive deficits. This was surprising as ARID1B is a common gene mutated in patients with intellectual disability and learning difficulties are common in children with CSS and ASD 4,9,82 . This may reflect the limitations with the mouse species as a model system or may reflect the high heterogeneity observed in human population.…”

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

“…A recent analysis of 143 patients with ARID1B mutations showed that individuals display a spectrum of clinical characteristics. Congenital heart defects were observed in 19.5% of the patients 44 .…”

Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development

“…By investigating learning and memory abilities that do not rely on high levels of movement and exploration, we avoided potential confounds regarding cognitive deficits, indicating that Arid1b +/mice were not impaired on motor-independent cognitive tasks. This was surprising as ARID1B is a common gene mutated in patients with intellectual disability, and learning difficulties are common in children with CSS and ASD [3,10,75]. This may reflect limitations with mice as a model system, or the high heterogeneity observed in human population.…”

“…In one study, the patient additionally had striking deficits in the brainstem and cerebellum which included ectopic neurons throughout the medulla, inferior olive, and cerebellar white matter [9]. In a recent report of 143 patients with ARID1B mutations, an agenesis or hypoplasia of the corpus callosum was prevalent in 43% of patients [10].…”