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.

Objective:To compare disease progression between different onset forms of Metachromatic Leukodystrophy (MLD) and to investigate the influence of the type of first symptoms on the natural course and dynamic of disease progression.Methods:Clinical, genetic and biochemical parameters were analyzed within a nationwide study of patients with late-infantile (LI, onset ≤ 2.5 years), early-juvenile (EJ, onset 2.6 - < 6 years), late-juvenile (LJ, onset 6 – < 16 years), and adult (onset ≥ 16 years) forms of MLD. First symptoms were categorized as motor symptoms only, cognitive symptoms only, or both.. Standardized clinical endpoints included loss of motor and language functions, as well as dysphagia/tube feeding.Results:97 Patients with MLD were enrolled. Patients with LI (n=35) and EJ (n=18) MLD exhibited similarly rapid disease progression, all starting with motor symptoms (with or without additional cognitive symptoms). In LJ (n=38) and adult-onset (n=6) patients, the course of the disease was as rapid as in the early-onset forms, when motor symptoms were present at disease onset, while patients with only cognitive symptoms at disease onset exhibited significantly milder disease progression, independent of their age at onset. A certain genotype-phenotype correlation was observed.Conclusions:In addition to age at onset, the type of first symptoms predicts the rate of disease progression in MLD. These findings are important for counselling and therapy.Classification of Evidence:This study provides Class II evidence that in patients with MLD, age at onset and the type of first symptoms predict the rate of disease progression.