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

Abstract

Purpose: Pathogenic 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.

Methods: Clinicians entered clinical data in an extensive web-based survey.

Results: 79 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.

Conclusion: There 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.

Keywords: ARID1B; Coffin–Siris syndrome; bias; intellectual disability.

Fig. 1. Overview of the location of pathogenic variants in ARID1B.

Numbers represent exon numbers and a graphical representation of in-frame and out-frame exons. When an exon ends with a complete codon, a vertical line is displayed. If it has one additional base an arrow to the left is displayed, and two additional bases are indicated by an arrow to the right. In-frame exons thus have the same boundary on both sides of the exon. Small variants (defined as events ≤20 bases) are identified by the arrows above the exon structure; larger variants are shown as lines under the intron–exon structure. All large events were deletions. Only unique variants are shown. Uninterrupted lines represent variants in ARID1B-CSS patients; interrupted lines represent variants in ARID1B-ID patients.

Fig. 2. Biometry and developmental milestones.

Histograms of the standard deviation score (SDS) of (a) height, n = 122; (b) weight, n = 92; and (c) occipitofrontal circumference (OFC), n = 105. (d) Cumulative distribution of the developmental milestones walking (n = 117) and sitting (n = 85) for ARID1B-CSS and ARID1B-ID. (e) Kaplan–Meier plot for the whole cohort of the age at which patients spoke their first words (n = 126). Confidence intervals of Kaplan–Meier plots are generated by R’s survfit function.

Fig. 3. Degree of intellectual disability and survival analyses of seizures and hypothyroidism.

(a) Intellectual disability (ID) category as assessed by the treating physician, n = 127; and (b) IQ scores (determined at different ages using different scales), n = 35 for ARID1B-CSS and ARID1B-ID patients. (c) Kaplan–Meier plot for age of onset of seizures, n = 37 and (d) Kaplan–Meier plot for the age at which hypothyroidism was diagnosed, n = 10. Confidence intervals of Kaplan–Meier plots are generated by R’s survfit function.