Case report: A novel JAK3 homozygous variant in a patient with severe combined immunodeficiency and persistent COVID-19

Abstract

Inborn errors of immunity (IEI) encompass a broad range of disorders with heterogeneous clinical presentations, often leading to challenges in early diagnosis. This study presents a case of a Brazilian patient with a T-B+NK- severe combined immunodeficiency (SCID) diagnosed at the age of 6 months when was admitted to the hospital due to multiple infectious diseases. Despite undergoing hematopoietic stem cell transplantation (HSCT), the patient had recurrent infections, requiring constant hospital care, including IgG infusions and several antibiotic treatments for the following months. One year after HSCT, presenting mixed chimerism, the patient tested positive for SARS-CoV-2 in nasopharyngeal, duodenum, and intestine samples, with persistent positive tests over a six-month period. Whole exome sequencing identified a private homozygous missense variant (c.1202T>C; p.Leu401Pro) in the Janus Kinase 3 (JAK3) gene. This substitution is located in a highly conserved position, and different bioinformatic variant effect predictors classified the variant as damaging. In silico structural analysis suggested that the variant led to increased structural instability, disrupting the hydrophobic interactions within the SH2 domain, thereby influencing the neighboring residues and potentially altering the interaction between JAK3 and gamma chain (γc) intracellular receptors. This study provides evidence for the novel pathogenicity classification of the variant and highlights the importance of the JAK3 and SH2 domain modulating protein function and their contribution to the SCID pathogenesis.

Keywords: JAK3; SCID; case report; inborn errors of immunity; prolonged SARS-CoV-2; whole exome sequencing.

Figure 1

Brazilian patient with SCID due to JAK3 deficiency. SCID case report findings, patient’s timeline describing relevance events, and related X-ray findings. In (A) Lung hyperinflation signs. Peribronchovascular bundles, especially in the central lung areas, along with faint heterogeneous opacities, primarily in the lower parts of the left lung and upper parts of the right lung. (B) Mild infiltration in the medullary region of the left lung, with no other evidence of pleuropulmonary alteration. (C) Mild thickening of bronchial walls and apparent splenomegaly can be seen. (D) JAK3 gene and protein. JAK3 gene comprises 24 exons (23 coding) that code seven Janus kinase homology domains (JH1-JH7) highlighting JH3 and JH4 together constitute the SH2-like domain, and JH4 domains constitute the FERM domain. (E) Family pedigree. (F) Multisequence alignment colored according to conservation scores, highlighting p.His377 and p.Leu401. (G) Electropherogram showing the variant’s segregation pattern on the kindred (Y= C+T). (H) 3D structure of JAK3 SH2 domain. (I) 3D stick structure of residues under a distance of 4 angstroms of p.Leu401 (left) and p.Pro401 (right).