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Abstract：
Most patients with childhood-onset immune dysregulation, polyendocrinopathy, and enteropathy have no genetic diagnosis for their illness. These patients may undergo empirical immunosuppressive treatment with highly variable outcomes.
We sought to determine the genetic basis of disease in patients referred with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like (IPEX-like) disease, but with no mutation in FOXP3; then to assess consequences of genetic diagnoses for clinical management.
Genomic DNA was sequenced using a panel of 462 genes implicated in inborn errors of immunity. Candidate mutations were characterized by genomic, transcriptional, and (for some) protein analysis.
Of 123 patients with FOXP3-negative IPEX-like disease, 48 (39%) carried damaging germline mutations in 1 of the following 27 genes: AIRE, BACH2, BCL11B, CARD11, CARD14, CTLA4, IRF2BP2, ITCH, JAK1, KMT2D, LRBA, MYO5B, NFKB1, NLRC4, POLA1, POMP, RAG1, SH2D1A, SKIV2L, STAT1, STAT3, TNFAIP3, TNFRSF6/FAS, TNRSF13B/TACI, TOM1, TTC37, and XIAP. Many of these genes had not been previously associated with an IPEX-like diagnosis. For 42 of the 48 patients with genetic diagnoses, knowing the critical gene could have altered therapeutic management, including recommendations for targeted treatments and for or against hematopoietic cell transplantation.
Many childhood disorders now bundled as \"IPEX-like\" disease are caused by individually rare, severe mutations in immune regulation genes. Most genetic diagnoses of these conditions yield clinically actionable findings. Barriers are lack of testing or lack of repeat testing if older technologies failed to provide a diagnosis.
We sought to determine the genetic basis of disease in patients referred with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like (IPEX-like) disease, but with no mutation in FOXP3; then to assess consequences of genetic diagnoses for clinical management.
Genomic DNA was sequenced using a panel of 462 genes implicated in inborn errors of immunity. Candidate mutations were characterized by genomic, transcriptional, and (for some) protein analysis.
Of 123 patients with FOXP3-negative IPEX-like disease, 48 (39%) carried damaging germline mutations in 1 of the following 27 genes: AIRE, BACH2, BCL11B, CARD11, CARD14, CTLA4, IRF2BP2, ITCH, JAK1, KMT2D, LRBA, MYO5B, NFKB1, NLRC4, POLA1, POMP, RAG1, SH2D1A, SKIV2L, STAT1, STAT3, TNFAIP3, TNFRSF6/FAS, TNRSF13B/TACI, TOM1, TTC37, and XIAP. Many of these genes had not been previously associated with an IPEX-like diagnosis. For 42 of the 48 patients with genetic diagnoses, knowing the critical gene could have altered therapeutic management, including recommendations for targeted treatments and for or against hematopoietic cell transplantation.
Many childhood disorders now bundled as \"IPEX-like\" disease are caused by individually rare, severe mutations in immune regulation genes. Most genetic diagnoses of these conditions yield clinically actionable findings. Barriers are lack of testing or lack of repeat testing if older technologies failed to provide a diagnosis.
摘要：
大多数儿童免疫失调的患者，多内分泌病,肠病没有基因诊断。这些患者可能接受经验性免疫抑制治疗，结果差异很大。
我们试图确定免疫失调患者疾病的遗传基础，多内分泌病,肠病,X连锁样（IPEX样）疾病，但FOXP3无突变;然后评估基因诊断对临床治疗的影响。
使用一组462个与先天免疫错误有关的基因对基因组DNA进行测序。候选突变的特征是基因组，转录，和（对于某些）蛋白质分析。
在123例FOXP3阴性IPEX样疾病患者中，48（39％）在以下27个基因中的1个中携带了破坏性的种系突变：AIRE，BACH2,BCL11B,CARD11,CARD14,CTLA4,IRF2BP2,ITCH,JAK1,KMT2D,LRBA,MYO5B,NFKB1,NLRC4,POLA1,POMP,RAG1,SH2D1A,SKIV2L,STAT1,STAT3,TNFAIP3,TNFRSF6/FAS,TNRSF13B/TACI、TOM1、TTC37和XIAP。这些基因中的许多基因以前与IPEX样诊断无关。对于48例基因诊断患者中的42例，知道关键基因可能会改变治疗管理，包括靶向治疗和支持或反对造血细胞移植的建议。
现在被捆绑为“IPEX样”疾病的许多儿童疾病都是由个别罕见的疾病引起的，免疫调节基因的严重突变。这些病症的大多数遗传诊断产生临床上可操作的发现。如果旧技术未能提供诊断，则障碍是缺乏测试或缺乏重复测试。
我们试图确定免疫失调患者疾病的遗传基础，多内分泌病,肠病,X连锁样（IPEX样）疾病，但FOXP3无突变;然后评估基因诊断对临床治疗的影响。
使用一组462个与先天免疫错误有关的基因对基因组DNA进行测序。候选突变的特征是基因组，转录，和（对于某些）蛋白质分析。
在123例FOXP3阴性IPEX样疾病患者中，48（39％）在以下27个基因中的1个中携带了破坏性的种系突变：AIRE，BACH2,BCL11B,CARD11,CARD14,CTLA4,IRF2BP2,ITCH,JAK1,KMT2D,LRBA,MYO5B,NFKB1,NLRC4,POLA1,POMP,RAG1,SH2D1A,SKIV2L,STAT1,STAT3,TNFAIP3,TNFRSF6/FAS,TNRSF13B/TACI、TOM1、TTC37和XIAP。这些基因中的许多基因以前与IPEX样诊断无关。对于48例基因诊断患者中的42例，知道关键基因可能会改变治疗管理，包括靶向治疗和支持或反对造血细胞移植的建议。
现在被捆绑为“IPEX样”疾病的许多儿童疾病都是由个别罕见的疾病引起的，免疫调节基因的严重突变。这些病症的大多数遗传诊断产生临床上可操作的发现。如果旧技术未能提供诊断，则障碍是缺乏测试或缺乏重复测试。
