Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
Nat Commun. 2020 Feb 21;11(1):995. doi: 10.1038/s41467-019-14275-y.
Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing 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), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.
早发性炎症性肠病（VEO-IBD）是一种与一系列罕见孟德尔疾病相关的异质性表型。在这里，我们对 145 名患者（中位诊断年龄为 3.5 岁）进行了全外显子组测序和全基因组基因分型，这些患者均未临床怀疑有孟德尔疾病。在五名患者中，我们检测到一种原发性免疫缺陷或肠病，具有临床后果（XIAP、CYBA、SH2D1A、PCSK1）。我们还介绍了一名 VEO-IBD 患者的病例研究，该患者在 CYBB 中存在嵌合体新生、致病性等位基因。该突变存在于约 70%的吞噬细胞中，足以导致细菌处理缺陷，但不会导致危及生命的感染。最后，我们发现 VEO-IBD 患者的 IBD 多基因风险评分高于普通人群对照（99 名患者和 18780 名对照；P<4×10），并在另一组 VEO-IBD 病例和对照中验证了这一发现（117 名患者和 2603 名对照；P<5×10）。这一发现表明，多基因成分在 VEO-IBD 的发病机制中起作用。
