Novel de novo dominant <i>PSMB10</i> variants in three patients with immune deficiency and liver disease

Background and objective: Despite significant advances, the molecular basis and thus patient-tailored therapeutic options for inborn errors of immunity remain unknown in a significant number of patients. Methods: We investigated three patients from unrelated families with inborn errors of immunity and severe liver disease. Clinical, immunological, and histological (only in one patient for the latter) data were collected, and trio whole exome sequencing was performed. Results: Whole exome sequencing identified heterozygous de novo variants in PSMB10 (p.Asp205Ala and p.Ser208Phe), a gene encoding a specific subunit of the immuno- and thymoproteasome. Analysis showed poor integration into the proteasome complex of PSMB10 variants, thereby exerting a dominant-negative effect on the PSMB9 subunit. Conclusion: Dominant PSMB10 variants should be considered in genetic screening for SCID and CID, especially in patients with associated liver disease. Very severe endothelial-like disease before and after HSCT and very poor outcomes after HSCT should weigh up the indication of HSCT.