Firtina Sinem, Ng Yuk Yin, Ng Ozden H, Kiykim Ayca, Ozek Esra Yucel, Kara Manolya, Aydiner Elif, Nepesov Serdar, Camcioglu Yildiz, Sayar Esra H, Gungoren Ezgi Yalcin, Reisli Ismail, Torun Selda H, Haskologlu Sule, Cogurlu Tuba, Kaya Aysenur, Cekic Sukru, Baris Safa, Ozbek Ugur, Ozen Ahmet, Sayitoglu Muge
Istanbul University Graduate School of Health Sciences, Istanbul, Turkey.
Department of Bioinformatics and Genetics, Engineering and Natural Sciences Faculty, Istinye University, Istanbul, Turkey.
Immunol Res. 2022 Feb;70(1):44-55. doi: 10.1007/s12026-021-09242-z. Epub 2021 Oct 7.
Primary antibody deficiencies (PAD) are the most common subtype of primary immunodeficiencies, characterized by increased susceptibility to infections and autoimmunity, allergy, or malignancy predisposition. PAD syndromes comprise of immune system genes highlighted the key role of B cell activation, proliferation, migration, somatic hypermutation, or isotype switching have a wide spectrum from agammaglobulinemia to selective Ig deficiency. In this study, we describe the molecular and the clinical aspects of fifty-two PAD patients. The most common symptoms of our cohort were upper and lower respiratory infections, bronchiectasis, diarrhea, and recurrent fever. Almost all patients (98%) had at least one of the symptoms like autoimmunity, lymphoproliferation, allergy, or gastrointestinal disease. A custom-made next-generation sequencing (NGS) panel, which contains 24 genes, was designed to identify well-known disease-causing variants in our cohort. We identified eight variants (15.4%) among 52 PAD patients. The variants mapped to BTK (n = 4), CD40L (n = 1), ICOS (n = 1), IGHM (n = 1), and TCF3 (n = 1) genes. Three novel variants were described in the BTK (p.G414W), ICOS (p.G60*), and IGHM (p.S19*) genes. We performed Sanger sequencing to validate pathogenic variants and check for allelic segregation in the family. Targeted NGS panel sequencing can be beneficial as a suitable diagnostic modality for diagnosing well-known monogenic PAD diseases (only 2-10% of PADs); however, screening only the coding regions of the genome may not be adequately powered to solve the pathogenesis of PAD in all cases. Deciphering the regulatory regions of the genome and better understanding the epigenetic modifications will elucidate the molecular basis of complex PADs.
原发性抗体缺陷（PAD）是原发性免疫缺陷最常见的亚型，其特征是易患感染、自身免疫性疾病、过敏或有患恶性肿瘤的倾向。PAD综合征由免疫系统基因组成，这些基因突出了B细胞激活、增殖、迁移、体细胞超突变或同种型转换的关键作用，其范围从无丙种球蛋白血症到选择性Ig缺陷。在本研究中，我们描述了52例PAD患者的分子和临床情况。我们队列中最常见的症状是上、下呼吸道感染、支气管扩张、腹泻和反复发热。几乎所有患者（98%）都有自身免疫、淋巴细胞增殖、过敏或胃肠道疾病等至少一种症状。设计了一个包含24个基因的定制下一代测序（NGS）面板，以识别我们队列中已知的致病变异。我们在52例PAD患者中鉴定出8个变异（15.4%）。这些变异定位于BTK（n = 4）、CD40L（n = 1）、ICOS（n = 1）、IGHM（n = 1）和TCF3（n = 1）基因。在BTK（p.G414W）、ICOS（p.G60*）和IGHM（p.S19*）基因中描述了3个新变异。我们进行了桑格测序以验证致病变异并检查家族中的等位基因分离情况。靶向NGS面板测序作为诊断已知单基因PAD疾病（仅占PAD的2 - 10%）的合适诊断方法可能是有益 的；然而，仅筛查基因组的编码区域可能不足以在所有情况下解决PAD的发病机制。解读基因组的调控区域并更好地理解表观遗传修饰将阐明复杂PAD的分子基础。
