Omenn syndrome in two infants with different hypomorphic variants in Janus kinase 3

Christo Tsilifis, Jarmila Stremenova Spegarova, Ross Good, Helen Griffin, Karin R Engelhardt, Sophie Graham, Stephen Hughes, Peter Arkwright, Sophie Hambleton, Andrew R Gennery

Research output: Contribution to journalArticlepeer-review


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 JAK3R431P 36 variant in Omenn syndrome. Immunophenotyping of PBMC from the patient with the novel JAK3R431P 37 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 JAK3R775H 41 variant, and the second had a novel JAK3R431P variant. One patient with a novel JAK3R431P 42 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 JAK3R431P 45 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.
Original languageEnglish
JournalJournal of Clinical Immunology
Issue number98
Publication statusPublished - 10 Apr 2024


  • Severe combined immunodeficiency
  • Omenn syndrome
  • haematopoietic stem cell transplant
  • Janus kinase 3


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