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首页> 外文期刊>BMC Medical Genomics >Whole exome sequencing in three families segregating a pediatric case of sarcoidosis
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Whole exome sequencing in three families segregating a pediatric case of sarcoidosis

机译：三个家庭的全外显子组测序分离出结节病的小儿病例

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Sarcoidosis (OMIM 181000) is a multi-systemic granulomatous disorder of unknown origin. Despite multiple genome-wide association (GWAS) studies, no major pathogenic pathways have been identified to date. To find out relevant sarcoidosis predisposing genes, we searched for de novo and recessive mutations in 3 young probands with sarcoidosis and their healthy parents using a whole-exome sequencing (WES) methodology. From the SARCFAM project based on a national network collecting familial cases of sarcoidosis, we selected three families (trios) in which a child, despite healthy parents, develop the disease before age 15?yr. Each trio was genotyped by WES (Illumina HiSEQ 2500) and we selected the gene variants segregating as 1) new mutations only occurring in affected children and 2) as recessive traits transmitted from each parents. The identified coding variants were compared between the three families. Allelic frequencies and in silico functional results were analyzed using ExAC, SIFT and Polyphenv2 databases. The clinical and genetic studies were registered by the ClinicalTrials.gov - Protocol Registration and Results System (PRS)?( https://clinicaltrials.gov ) receipt under the reference NCT02829853 and has been approved by the ethical committee (CPP LYON SUD EST – 2 – REF IRB 00009118 – September 21, 2016). We identified 37 genes sharing coding variants occurring either as recessive mutations in at least 2 trios or de novo mutations in one of the three affected children. The genes were classified according to their potential roles in immunity related pathways: 9 to autophagy and intracellular trafficking, 6 to G-proteins regulation, 4 to T-cell activation, 4 to cell cycle and immune synapse, 2 to innate immunity. Ten of the 37 genes were studied in a bibliographic way to evaluate the functional link with sarcoidosis. Whole exome analysis of case-parent trios is useful for the identification of genes predisposing to complex genetic diseases as sarcoidosis. Our data identified 37 genes that could be putatively linked to a pediatric form of sarcoidosis in three trios. Our in-depth focus on 10 of these 37 genes may suggest that the formation of the characteristic lesion in sarcoidosis, granuloma, results from combined deficits in autophagy and intracellular trafficking (ex: Sec16A, AP5B1 and RREB1), G-proteins regulation (ex: OBSCN, CTTND2 and DNAH11), T-cell activation (ex: IDO2, IGSF3), mitosis and/or immune synapse (ex: SPICE1 and KNL1). The significance of these findings needs to be confirmed by functional tests on selected gene variants.
机译：结节病（OMIM 181000）是一种未知来源的多系统肉芽肿性疾病。尽管进行了多个全基因组关联（GWAS）研究，但迄今为止尚未发现主要的致病途径。为了找出相关的结节病易感基因，我们使用全外显子测序（WES）方法在3个结节病的年轻先证者及其健康父母中搜索了从头突变和隐性突变。从基于全国网络收集结节病家庭病例的SARCFAM项目中，我们选择了三个家庭（三重家庭），尽管父母健康，孩子仍会在15岁之前患上该病。每个三人都通过WES（Illumina HiSEQ 2500）进行基因分型，我们选择了分离为1）仅在患病儿童中发生的新突变和2）作为从父母双方传播的隐性性状的基因变异。在三个家族之间比较了鉴定出的编码变体。使用ExAC，SIFT和Polyphenv2数据库分析了等位基因频率和计算机模拟功能结果。临床和基因研究已由ClinicalTrials.gov-方案注册和结果系统（PRS）？（https://clinicaltrials.gov）收据进行了注册，编号为NCT02829853，并已获得伦理委员会（CPP LYON SUD EST – 2 – REF IRB 00009118 – 2016年9月21日）。我们确定了37个共享编码变体的基因，这些变体要么是至少2个三重奏中的隐性突变，要么是三个受影响儿童之一的从头突变。根据基因在免疫相关途径中的潜在作用对基因进行分类：9是自噬和细胞内运输，6是G蛋白调节，4是T细胞活化，4是细胞周期和免疫突触，2是先天免疫。以书目方式研究了37个基因中的10个，以评估结节病的功能联系。病例-父母三重奏的整个外显子组分析可用于鉴定易患结节病等复杂遗传疾病的基因。我们的数据确定了可能在三个三态中与小儿结节病形式相关的37个基因。我们深入研究这37个基因中的10个，可能表明结节病，肉芽肿中特征性病变的形成是由于自噬和细胞内运输综合缺陷（例如：Sec16A，AP5B1和RREB1），G蛋白调节（例如：OBSCN，CTTND2和DNAH11），T细胞活化（例如IDO2，IGSF3），有丝分裂和/或免疫突触（例如SPICE1和KNL1）。这些发现的意义需要通过对所选基因变异进行功能测试来确认。

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