Exome sequencing analysis reveals variants in primary immunodeficiency genes in patients with very early onset inflammatory bowel disease.
Exome sequencing analysis reveals variants in primary immunodeficiency genes in patients with very early onset inflammatory bowel disease.
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DOI：
10.1053/j.gastro.2015.07.006
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发表时间：
2015-11
期刊：
影响因子：
29.4
通讯作者：
Devoto M
中科院分区：
文献类型：
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作者：
Kelsen JR;Dawany N;Moran CJ;Petersen BS;Sarmady M;Sasson A;Pauly-Hubbard H;Martinez A;Maurer K;Soong J;Rappaport E;Franke A;Keller A;Winter HS;Mamula P;Piccoli D;Artis D;Sonnenberg GF;Daly M;Sullivan KE;Baldassano RN;Devoto M
5岁时诊断为≤的极早发型炎症性肠病通常表现出不同于老年期炎症性肠病的表型。我们调查了VEO-IBD患者是否携带与可能导致疾病发展的免疫缺陷相关的罕见或新的基因变异。VEO-IBD患者和父母(如果有的话)是从2013年3月到2014年7月从费城儿童医院招募的。我们分析了125名VEO-IBD患者(年龄3周至4岁)和19名父母的DNA，其中4人也患有IBD。外显子组捕获用Agilent SureSelect V4进行，测序用Illumina HiSeq平台进行。实现了与人类基因组GRCH37的比对，并进行了后处理和变异体调用。在功能注释之后，分析候选变异的蛋白质功能、次要等位基因频率和0.1%的变化，并对联合注释依赖的耗竭评分≤10进行评分。我们重点关注与初级免疫缺陷相关的基因和相关途径。另取自德国基尔大学的儿童IBD患者(n=45)、成人克罗恩病患者(n=20)和健康人(n=145)的210个外显子样本作为对照组。从整个外显子组数据中选择了400个与初级免疫缺陷相关的基因和区域，覆盖了大约6500个编码外显子，总计1个MBP的编码序列。我们的分析揭示了这些基因中可能有助于VEO-IBD发展的新的和罕见的变异，包括IL10RA中罕见的杂合错义变异以及以前未识别的MSH5和CD19变异。在对VEO-IBD患者及其父母的外显子组序列分析中，我们发现了调节B细胞和T细胞功能并可能参与发病的基因的变异。我们的分析可能导致识别以前未识别的IBD相关变异。
Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed ≤5 y of age, frequently presents with a different and more severe phenotype than older-onset IBD. We investigated whether patients with VEO-IBD carry rare or novel variants in genes associated with immunodeficiencies that might contribute to disease development. Patients with VEO-IBD and parents (when available) were recruited from the Children's Hospital of Philadelphia from March 2013 through July 2014. We analyzed DNA from 125 patients with VEO-IBD (ages 3 weeks to 4 y) and 19 parents, 4 of whom also had IBD. Exome capture was performed by Agilent SureSelect V4, and sequencing was performed using the Illumina HiSeq platform. Alignment to human genome GRCh37 was achieved followed by post-processing and variant calling. Following functional annotation, candidate variants were analyzed for change in protein function, minor allele frequency <0.1%, and scaled combined annotation dependent depletion scores ≤10. We focused on genes associated with primary immunodeficiencies and related pathways. An additional 210 exome samples from patients with pediatric IBD (n=45) or adult-onset Crohn's disease (n=20) and healthy individuals (controls, n=145) were obtained from the University of Kiel, Germany and used as control groups. Four-hundred genes and regions associated with primary immunodeficiency, covering approximately 6500 coding exons totaling > 1 Mbp of coding sequence, were selected from the whole exome data. Our analysis revealed novel and rare variants within these genes that could contribute to the development of VEO-IBD, including rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19. In an exome sequence analysis of patients with VEO-IBD and their parents, we identified variants in genes that regulate B- and T-cell functions and could contribute to pathogenesis. Our analysis could lead to the identification of previously unidentified IBD-associated variants.