原發性免疫缺陷人群的全基因組測序
作者：
小柯機器人發布時間：2020/5/7 13:08:38
英國劍橋大學Paul A. Lyons和James E. D. Thaventhiran研究團隊合作取得新進展。他們進行了零星的原發性免疫缺陷人群的全基因組測序。2020年5月6日的《自然》雜誌發表了這一成果。
他們通過在1,318名參與者的大型原發性免疫缺陷（PID）研究中運用全基因組測序來解決一些挑戰。對886例PID病例的基因組編碼區進行分析發現，這些基因中涉及單基因PID的已知基因的致病突變發生在10.3％的患者中，並且貝葉斯方法（BeviMed4）確定了多個新的候選PID -相關基因，包括IVNS1ABP。
他們還分析了非編碼基因組，發現調節區的缺失是疾病發生的原因。此外，他們使用了全基因組關聯研究來鑑定與PID相關的基因座，並找到了新的高滲透性單基因變異體和常見變異體（在PTPN2和SOCS1基因座上）共定位以及相互作用的證據。這解釋了常見變異體對PID中觀察到的可變滲透率和表型複雜性的貢獻。因此，在PID的診斷中使用基於研究的全基因組測序方法可以提高診斷率，並進一步使人們了解影響人類免疫應答的關鍵途徑。
據了解，PID的特徵是易復發且導致感染甚至威脅生命，造成自身免疫和癌症，並且構成主要的診斷和治療挑戰。儘管最嚴重的PID形式是在兒童早期就發現的，但大多數患者是成年後出現的，通常沒有明顯的家族史，並且臨床表型具有廣泛的免疫失調的特徵。大約25％的患者患有自身免疫性疾病，過敏現象普遍存在，並且高達10％發生淋巴樣惡性腫瘤。因此，在散發性（或非家族性）PID中，遺傳診斷很困難，並且遺傳學的作用尚不明確。
附：英文原文
Title: Whole-genome sequencing of a sporadic primary immunodeficiency cohort
Author: James E. D. Thaventhiran, Hana Lango Allen, Oliver S. Burren, William Rae, Daniel Greene, Emily Staples, Zinan Zhang, James H. R. Farmery, Ilenia Simeoni, Elizabeth Rivers, Jesmeen Maimaris, Christopher J. Penkett, Jonathan Stephens, Sri V. V. Deevi, Alba Sanchis-Juan, Nicholas S. Gleadall, Moira J. Thomas, Ravishankar B. Sargur, Pavels Gordins, Helen E. Baxendale, Matthew Brown, Paul Tuijnenburg, Austen Worth, Steven Hanson, Rachel J. Linger, Matthew S. Buckland, Paula J. Rayner-Matthews, Kimberly C. Gilmour, Crina Samarghitean, Suranjith L. Seneviratne, David M. Sansom, Andy G. Lynch, Karyn Megy, Eva Ellinghaus, David Ellinghaus, Silje F. Jorgensen, Tom H. Karlsen, Kathleen E. Stirrups, Antony J. Cutler, Dinakantha S. Kumararatne, Anita Chandra, J. David M. Edgar, Archana Herwadkar, Nichola Cooper, Sofia Grigoriadou, Aarnoud P. Huissoon, Sarah Goddard, Stephen Jolles, Catharina Schuetz, Felix Boschann, Paul A. Lyons
Issue&Volume: 2020-05-06
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 malignancies1,2,3. 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.
DOI: 10.1038/s41586-020-2265-1
Source: https://www.nature.com/articles/s41586-020-2265-1