Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exomesequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10 −10 ), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10 −10 ). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.

No abstract

Some epigenetic information can be transmitted between generations without changes in the underlying DNA sequence. Changes in epigenetic regulators, termed epimutations, can occur spontaneously and be propagated in populations in a manner reminiscent of DNA mutations. Small RNA-based epimutations occur in C. elegans and persist for around 3–5 generations on average. Here, we explored whether chromatin states also undergo spontaneous change and whether this could be a potential alternative mechanism for transgenerational inheritance of gene expression changes. We compared the chromatin and gene expression profiles at matched time points from three independent lineages of C. elegans propagated at minimal population size. Spontaneous changes in chromatin occurred in around 1% of regulatory regions each generation. Some were heritable epimutations and were significantly enriched for heritable changes in expression of nearby protein-coding genes. Most chromatin-based epimutations were short-lived but a subset had longer duration. Genes subject to long-lived epimutations were enriched for multiple components of xenobiotic response pathways. This points to a possible role for epimutations in adaptation to environmental stressors.

Ibrexafungerp (formerly SCY-078), a novel glucan synthase inhibitor with oral availability, was evaluated for activity against Candida glabrata. The susceptibility of clinical strains to ibrexafungerp was determined by microdilution and time-kill assays. The MIC range against wild-type strains was 1 to 2 μg/ml. Ibrexafungerp was also active against the majority of echinocandin-resistant strains. Time-kill studies showed 4- to 6-log-unit reductions in growth at 24 and 48 h with concentrations of 0.25 to 4 μg/ml.