Introduction: Severe combined immunodeficiency (SCID) is a condition in which defects in lymphocyte development lead to increased susceptibility and severity of infections. T-B+NK- phenotype SCIDs are often caused by pathogenic variants in IL2RG or JAK3 genes. Here, we report the molecular investigation in a T-B+NK- patient with persistent Covid-19.
Case Report: At 6 months of age, a boy born to consanguineous parents (Brazilians) was admitted to the intensive care unit with pneumonia and BCG-itis. T-B+NK- SCID was diagnosed through immunophenotyping and the patient underwent haploidentical hematopoietic stem cell transplantation (HSCT) at 13 months age from his father. One year after HSCT, presenting mixed chimerism (around 19%), the patient tested positive for SARS-CoV-2 presenting respiratory and intestinal symptoms. The infection persisted for six months with positive PCR results in different tissues and viable viral particles. Through whole-exome sequencing, a private homozygous missense variant c.1202T>C (p.Leu401Pro), was identified in JAK3 gene. Variant segregation showed that both parents and his healthy brother are heterozygotes for this variant. In silico analysis, the p.Leu401Pro variant occurs at a conserved position, within the SH2 domain and it is predicted to disrupt protein function likely through both domain intrinsic disorder and an increase in protein stability. Discussion: Both the SH2 and FERM domains

mediate JAK3’s interaction with the intracellular portion of the gamma chain receptors, necessary for downstream signaling. Supporting the functional significance of this region, the residue at position 377, which forms a hydrogen bond with Leu401, has a reported missense pathogenic variant associated with SCID. Furthermore, all in silico tools applied predicted that the p.Leu401Pro variant results in protein damage. Conclusion: In this scenario, WES was useful to find genetic disease and we consider reclassifying this new JAK3 variant as likely pathogenic.
Institutional Review Board number 63844722.8.0000.5327.