Department of Medical Genetics, Faculty of Medicine, Balcali Hospital and Clinics, Cukurova University, Adana, Turkey.
Cukurova University AGENTEM (Adana Genetic Diseases Diagnosis and Treatment Center), Adana, Turkey.
Sci Rep. 2021 Apr 15;11(1):8308. doi: 10.1038/s41598-021-87898-1.
Next Generation Sequencing (NGS) has uncovered hundreds of common and rare genetic variants involved in complex and rare diseases including immune deficiencies in both an autosomal recessive and autosomal dominant pattern. These rare variants however, cannot be classified clinically, and common variants only marginally contribute to disease susceptibility. In this study, we evaluated the multi-gene panel results of Common Variable Immunodeficiency (CVID) patients and argue that rare variants located in different genes play a more prominent role in disease susceptibility and/or etiology. We performed NGS on DNA extracted from the peripheral blood leukocytes from 103 patients using a panel of 19 CVID-related genes: CARD11, CD19, CD81, ICOS, CTLA4, CXCR4, GATA2, CR2, IRF2BP2, MOGS, MS4A1, NFKB1, NFKB2, PLCG2, TNFRSF13B, TNFRSF13C, TNFSF12, TRNT1 and TTC37. Detected variants were evaluated and classified based on their impact, pathogenicity classification and population frequency as well as the frequency within our study group. NGS revealed 112 different (a total of 227) variants with under 10% population frequency in 103 patients of which 22(19.6%) were classified as benign, 29(25.9%) were classified as likely benign, 4(3.6%) were classified as likely pathogenic and 2(1.8%) were classified as pathogenic. Moreover, 55(49.1%) of the variants were classified as variants of uncertain significance. We also observed different variant frequencies when compared to population frequency databases. Case-control data is not sufficient to unravel the genetic etiology of immune deficiencies. Thus, it is important to understand the incidence of co-occurrence of two or more rare variants to aid in illuminating their potential roles in the pathogenesis of immune deficiencies.
下一代测序（NGS）已经发现了数百种与复杂和罕见疾病相关的常见和罕见遗传变异，包括常染色体隐性和常染色体显性遗传模式下的免疫缺陷。然而，这些罕见变异不能进行临床分类，常见变异仅对疾病易感性有微小贡献。在这项研究中，我们评估了常见可变免疫缺陷（CVID）患者的多基因panel 结果，并认为位于不同基因中的罕见变异在疾病易感性和/或病因学中发挥更重要的作用。我们使用包含 19 个 CVID 相关基因的panel（CARD11、CD19、CD81、ICOS、CTLA4、CXCR4、GATA2、CR2、IRF2BP2、MOGS、MS4A1、NFKB1、NFKB2、PLCG2、TNFRSF13B、TNFRSF13C、TNFSF12、TRNT1 和 TTC37）对来自 103 名患者的外周血白细胞 DNA 进行了 NGS。根据其影响、致病性分类和人群频率以及我们研究组内的频率，对检测到的变异进行了评估和分类。在 103 名患者中，NGS 共发现了 112 种不同的（共计 227 种）频率低于 10%的变异，其中 22 种（19.6%）被归类为良性，29 种（25.9%）被归类为可能良性，4 种（3.6%）被归类为可能致病性，2 种（1.8%）被归类为致病性。此外，55 种（49.1%）变异被归类为意义不明的变异。我们还观察到与人群频率数据库相比，变异频率有所不同。病例对照数据不足以揭示免疫缺陷的遗传病因。因此，了解两个或更多罕见变异同时发生的频率对于阐明它们在免疫缺陷发病机制中的潜在作用非常重要。
