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

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

Epithelial mesenchymal transition in the progression of renal disease in dogs

Chronic kidney disease (CKD) in dogs is the final common pathway resulting from persistent renal injury and is characterized by progressive tubulointerstitial damage (TID). Pathogenesis of CKD is divided into an initial inflammatory phase with a predominantly mononuclear infiltrate followed by a fibrotic phase with increased numbers of fibroblasts and extracellular matrix deposition that causes a progressive reduction of functional parenchyma. Proteinuria is a common manifestation of renal diseases in dogs, and its role in the pathogenesis of CKD is still uncertain. Nevertheless, the degree of proteinuria in dogs correlates with TID progression. Increased protein filtration may have direct effects on tubular epithelial cells (TECs) that induce them to express the major histocompatibility complex type II, and thereby contribute to lymphocyte recruitment. Thus, an active pro-inflammatory role is proposed for TECs in TID progression. Moreover TECs are believed to actively participate in the mechanisms of renal fibrosis. Epithelial-Mesenchymal-Transition (EMT) of TECs in canine TID has been studied in the last decade. Downregulation of adhesion molecules and loss of epithelial markers in TECs directly correlate with the severity of TID and with de novo expression of mesenchymal markers. Tubular basement membrane (TBM) disruption is an early EMT event. Increased activity of Matrix Metalloproteinase-2 and its co-localization with TBM splitting suggests an active role for the enzyme in inducing EMT. Processes occurring in canine CKD share many similarities with its human counterpart, making the dog a good model in which to examine the mechanisms of TID progression