Mutations in the common gamma chain of the interleukin 2 receptor (IL2RG) or the associated downstream signaling enzyme Janus kinase 3 (JAK3) genes are typically characterized by a T cell-negative, B cell-positive, natural killer (NK) cell-negative (T⁻B⁺NK⁻) severe combined immunodeficiency (SCID) immune phenotype. We report clinical course, immunological, genetic and proteomic work-up of two patients with different novel mutations in the IL-2-JAK3 pathway with a rare atypical presentation of T⁻B⁺NK⁻ SCID. Lymphocyte subpopulation revealed significant T cells lymphopenia, normal B cells, and NK cells counts (T−B+NK+SCID). Despite the presence of B cells, IgG levels were low and IgA and IgM levels were undetectable. T-cell proliferation in response to mitogens in patient 1 was very low and T-cell receptor V-beta chain repertoire in patient 2 was polyclonal. Whole-exome sequencing revealed novel mutations in both patients (patient 1—c.923delC frame-shift mutation in the IL2RG gene, patient 2—c.G172A a homozygous missense mutation in the JAK3 gene). Bioinformatic analysis of the JAK3 mutation indicated deleterious effect and 3D protein modeling located the mutation to a surface exposed alpha-helix structure. Our findings help to link between genotype and phenotype, which is a key factor for the diagnosis and treatment of SCID patients.

白细胞介素 2 受体 (IL2RG) 或相关下游信号酶 Janus 激酶 3 (JAK3) 基因的共同 γ 链中的突变通常以 T 细胞阴性、B 细胞阳性、自然杀伤 (NK) 细胞阴性为特征(T ^- B ⁺ NK ^- ) 严重联合免疫缺陷 (SCID) 免疫表型。我们报告了两名在 IL-2-JAK3 通路中具有不同新突变的患者的临床病程、免疫学、遗传学和蛋白质组学检查，并具有罕见的非典型 T ^- B ⁺ NK ^{- 表现。}SCID。淋巴细胞亚群显示显着的 T 细胞淋巴细胞减少、正常 B 细胞和 NK 细胞计数（T-B+NK+SCID）。尽管存在 B 细胞，但 IgG 水平很低，并且检测不到 IgA 和 IgM 水平。患者 1 中响应促分裂原的 T 细胞增殖非常低，而患者 2 中的 T 细胞受体 V-β 链库是多克隆的。全外显子组测序揭示了两名患者的新突变（患者 1 - IL2RG 基因中的 c.923delC 移码突变，患者 2 - JAK3 基因中的 c.G172A 纯合错义突变）。JAK3 突变的生物信息学分析表明有害作用和 3D 蛋白质建模将突变定位到表面暴露的 α 螺旋结构。我们的发现有助于将基因型和表型联系起来，这是诊断和治疗 SCID 患者的关键因素。