PDF(Pubmed)
Abstract：
CARD11-associated diseases are monogenic inborn errors of immunity involving immunodeficiency, predisposition to malignancy and immune dysregulation such as lymphoproliferation, inflammation, atopic and autoimmune manifestations. Defects in CARD11 can present as mutations that confer a complete or a partial loss of function (LOF) or contrarily, a gain of function (GOF) of the affected gene product. We report clinical characteristics, immunophenotypes and genotypes of 15 patients from our center presenting with CARD11-associated diseases. Index cases are pediatric patients followed in our immunology division who had access to next generation sequencing studies. Variant significance was defined by functional analysis in cultured cells transfected with a wild type and/or with mutated hCARD11 constructs. Cytoplasmic aggregation of CARD11 products was evaluated by immunofluorescence. Nine index patients with 9 unique heterozygous CARD11 variants were identified. At the time of the identification, 7 variants previously unreported required functional validation. Altogether, four variants showed a GOF effect as well a spontaneous aggregation in the cytoplasm, leading to B cell expansion with NF-κB and T cell anergy (BENTA) diagnosis. Additional four variants showing a LOF activity were considered as causative of CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS). The remaining variant exhibited a neutral functional assay excluding its carrier from further analysis. Family segregation studies expanded to 15 individuals the number of patients presenting CARD11-associated disease. A thorough clinical, immunophenotypical, and therapeutic management evaluation was performed on these patients (5 BENTA and 10 CADINS). A remarkable variability of disease expression was clearly noted among BENTA as well as in CADINS patients, even within multiplex families. Identification of novel CARD11 variants required functional studies to validate their pathogenic activity. In our cohort BENTA phenotype exhibited a more severe and expanded clinical spectrum than previously reported, e.g., severe hematological and extra hematological autoimmunity and 3 fatal outcomes. The growing number of patients with dysmorphic facial features strengthen the inclusion of extra-immune characteristics as part of the CADINS spectrum. CARD11-associated diseases represent a challenging group of disorders from the diagnostic and therapeutic standpoint, especially BENTA cases that can undergo a more severe progression than previously described.
摘要：
CARD11相关疾病是涉及免疫缺陷的单基因先天性免疫错误，易患恶性肿瘤和免疫失调，如淋巴增生，炎症,特应性和自身免疫表现。CARD11中的缺陷可以表现为突变，赋予完全或部分功能丧失（LOF）或相反，受影响的基因产物的功能获得(GOF)。我们报告临床特征，我们中心15例CARD11相关疾病患者的免疫表型和基因型。索引病例是我们免疫学部门随访的儿科患者，他们可以进行下一代测序研究。通过在用野生型和/或用突变的hCARD11构建体转染的培养细胞中的功能分析来定义变体显著性。通过免疫荧光评估CARD11产物的细胞质聚集。鉴定了具有9个独特杂合CARD11变体的9个指标患者。在鉴定的时候,以前未报告的7种变体需要功能验证。总之,四种变体显示了GOF效应以及细胞质中的自发聚集，导致B细胞扩增与NF-κB和T细胞无反应性（BENTA）诊断。显示LOF活性的另外四个变体被认为是CARD11相关的特应性与NF-kB信号传导(CADINS)的显性干扰的原因。剩余的变体表现出中性功能测定,将其载体排除在进一步分析之外。家庭隔离研究将出现CARD11相关疾病的患者数量扩大到15个人。彻底的临床，免疫表型,并对这些患者进行治疗管理评估(5个BENTA和10个CADINS).在BENTA和CADINS患者中清楚地注意到疾病表达的显着变异性，甚至在多元家庭中。新型CARD11变体的鉴定需要功能研究以验证其致病活性。在我们的队列中，BENTA表型表现出比以前报道的更严重和扩展的临床谱，例如，严重的血液学和血液学外自身免疫和3个致命结局。越来越多的具有畸形面部特征的患者加强了作为CADINS谱的一部分的免疫外特征的纳入。从诊断和治疗的角度来看，CARD11相关疾病代表了一组具有挑战性的疾病，尤其是BENTA病例可以经历比以前描述的更严重的进展。
