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Whole-genome sequencing of a sporadic primary immunodeficiency cohort

机译：散发性主要免疫缺陷队列的全基因组测序

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Abstract Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1–3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of—and interplay between—novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
机译：摘要初级免疫缺陷（PID）的特征在于经常性，往往危及生命的感染，自身免疫和癌症，它带来了主要的诊断和治疗挑战。虽然最严重的PID形式在幼儿期内发现，大多数患者在成年期存在，通常没有明显的家族史和广泛的免疫失调的可变临床表型：约25％的患者具有自身免疫性疾病，过敏是普遍的，普遍存在10％发育淋巴瘤Malignancies1-3。因此，在散发性（或非家庭）的PID遗传诊断中难以明确地定义遗传学且遗传学的作用。在这里，我们通过在1,318名参与者的大型PID队列中进行全基因组测序来解决这些挑战。对886个PID指数案例的基因组的编码区分析发现，在这些患者的10.3％内牵连的已知基因中的疾病导致突变发生，贝叶斯方法（BEVIMED4）确定了多个新候选PID - 包括Ivns1abp，包括Ivns1abp的基因。我们还研究了非编码基因组，发现缺失在有助于疾病的监管区域。此外，我们使用了基因组 - 范围的关联研究来鉴定与PID相关的基因座，并发现了新型高渗透单生变体和常用变体之间的分层和相互作用的分层化的证据（在PTPN2和SOCS1基因座中）。这开始解释常见变体对PID中观察到的可变渗透和表型复杂性的贡献。因此，在PID的诊断中使用基于群组的全基因组测序方法可以提高诊断产量，并进一步了解影响人类免疫反应性的关键途径。

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    《Nature》 |2020年第7814期|90-95|共6页
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  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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