Watson Ashleigh, Harris R Alan, Engevik Amy C, Oezguen Numan, Nicholson Maribeth R, Dooley Sarah, Stubler Rachel, Satter Lisa Forbes, Karam Lina B, Kellermayer Richard
Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
Inflamm Bowel Dis. 2025 Jan 6;31(1):189-199. doi: 10.1093/ibd/izae169.
Genetic discovery in very early-onset inflammatory bowel disease (VEO-IBD) can elucidate not only the origins of VEO-IBD, but also later-onset inflammatory bowel disease. We aimed to investigate the polygenic origins of VEO-IBD in a cohort with a high proportion of Hispanic patients.
Patients with VEO-IBD who underwent whole exome sequencing at our center were included. Genes were categorized as genes of interest (GOIs) (129 genes previously described to be associated with VEO-IBD) or non-GOIs. VEO-IBD "susceptibility" single nucleotide variants (SNVs) were identified through enrichment compared with gnomAD (Genome Aggregation Database) and ALFA (Allele Frequency Aggregator) and were scored by Combined Annotation Dependent Depletion for deleteriousness. Gene networks carrying susceptibility SNVs were created. Myosin 5b immunofluorescence was also studied.
Fifty-six patients met inclusion criteria, and 32.1% identified as Hispanic. Monogenic disease was infrequent (8.9%). Significant enrichment of GOI susceptibility SNVs was observed, notably in MYO5B, especially in Hispanics. MEFV, TNFAIP3, SH3TC2, and NCF2 were also central participants in the GOI networks. Myosin 5b immunofluorescence in colonic mucosa was significantly reduced in those with MYO5B susceptibility SNVs compared with control subjects. Seven genes (ESRRA, HLA-DQ1, RETSAT, PABPC1, PARP4, CCDC102A, and SUSD2) were central participants in the non-GOI networks.
Our results support the polygenic nature of VEO-IBD, in which key participants, like MYO5B, were identified through network analytics. Rare variant load within susceptibility genes may be relevant not only for the genetic origins of inflammatory bowel disease, but also for the age of disease onset. Our findings could guide future work in precision medicine.
极早发型炎症性肠病（VEO-IBD）的基因发现不仅可以阐明VEO-IBD的起源，还能揭示晚发型炎症性肠病的起源。我们旨在研究一个西班牙裔患者比例较高的队列中VEO-IBD的多基因起源。
纳入在我们中心接受全外显子测序的VEO-IBD患者。基因被分类为感兴趣基因（GOIs）（先前描述的129个与VEO-IBD相关的基因）或非感兴趣基因。通过与gnomAD（基因组聚合数据库）和ALFA（等位基因频率聚合器）比较进行富集，识别VEO-IBD“易感性”单核苷酸变异（SNVs），并通过联合注释依赖损耗对有害性进行评分。构建携带易感性SNVs的基因网络。还研究了肌球蛋白5b免疫荧光。
56例患者符合纳入标准，32.1%为西班牙裔。单基因疾病不常见（8.9%）。观察到GOI易感性SNVs显著富集，尤其是在MYO5B中，在西班牙裔中尤为明显。MEFV、TNFAIP3、SH3TC2和NCF2也是GOI网络的核心参与者。与对照受试者相比，具有MYO5B易感性SNVs的患者结肠黏膜中的肌球蛋白5b免疫荧光显著降低。7个基因（ESRRA、HLA-DQ1、RETSAT、PABPC1、PARP4、CCDC102A和SUSD2）是非GOI网络的核心参与者。
我们的结果支持VEO-IBD的多基因性质，其中通过网络分析确定了关键参与者，如MYO5B。易感性基因内的罕见变异负荷不仅可能与炎症性肠病的遗传起源有关，还与疾病发病年龄有关。我们的发现可为精准医学的未来工作提供指导。
