Biallelic null or hypomorphic variants in JAK3 cause SCID and less frequently Omenn syndrome. We investigated homozygous hypomorphic JAK3 mutations in two patients, and expression and function of a novel JAK3^R431P variant in Omenn syndrome. Immunophenotyping of PBMC from the patient with the novel JAK3^R431P variant was undertaken, by flow cytometry and Phosflow after stimulation with IL-2, IL-7, and IL-15. JAK3 expression was investigated by Western blotting. We report two patients with homozygous hypomorphic JAK3 variants and clinical features of Omenn syndrome. One patient had a previously described JAK3^R775H variant, and the second had a novel JAK3^R431P variant. One patient with a novel JAK3^R431P variant had normal expression of JAK3 in immortalised EBV-LCL cells but reduced phosphorylation of STAT5 after stimulation with IL-2, IL-7, and IL-15 consistent with impaired kinase activity. These results suggest the JAK3^R431P variant to be hypomorphic. Both patients are alive and well after allogeneic haematopoietic stem cell transplantation. They have full donor chimerism, restitution of thymopoiesis and development of appropriate antibody responses following vaccination. We expand the phenotype of hypomorphic JAK3 deficiency and demonstrate the importance of functional testing of novel variants in disease-causing genes.

JAK3中的双等位基因无效或亚等位变异会导致 SCID 和较少见的 Omenn 综合征。我们研究了两名患者的纯合亚型 JAK3 突变，以及Omenn 综合征中新型 JAK3 ^R431P变体的表达和功能。在用 IL-2、IL-7 和 IL-15 刺激后，通过流式细胞术和 Phosflow对来自携带新型 JAK3 ^R431P变体的患者的 PBMC 进行免疫表型分析。通过蛋白质印迹研究JAK3表达。我们报告了两名具有纯合亚形性JAK3变异的患者和 Omenn 综合征的临床特征。一名患者患有先前描述的 JAK3 ^R775H变异，第二名患者患有新型 JAK3 ^R431P变异。一名携带新型 JAK3 ^R431P变异的患者在永生化 EBV-LCL 细胞中 JAK3 表达正常，但在用 IL-2、IL-7 和 IL-15 刺激后 STAT5 磷酸化降低，这与激酶活性受损一致。这些结果表明 JAK3 ^R431P变体是亚效型的。两名患者在接受同种异体造血干细胞移植后均存活且状况良好。它们具有完全的供体嵌合、胸腺生成的恢复以及疫苗接种后适当抗体反应的发展。我们扩展了低效型 JAK3 缺陷的表型，并证明了对致病基因中的新变异进行功能测试的重要性。