Enrichment of Immune Dysregulation Disorders in Adult Patients with Human Inborn Errors of Immunity

Abstract

Human inborn errors of immunity (IEI) comprise a group of diseases resulting from molecular variants that compromise innate and adaptive immunity. Clinical features of IEI patients are dominated by susceptibility to a spectrum of infectious diseases, as well as autoimmune, autoinflammatory, allergic, and malignant phenotypes that usually appear in childhood, which is when the diagnosis is typically made. However, some IEI patients are identified in adulthood due to symptomatic delay of the disease or other reasons that prevent the request for a molecular study. The application of next-generation sequencing (NGS) as a diagnostic technique has given rise to an ever-increasing identification of IEI-monogenic causes, thus improving the diagnostic yield and facilitating the possibility of personalized treatment. This work was a retrospective study of 173 adults with IEI suspicion that were sequenced between 2005 and 2023. Sanger, targeted gene-panel, and whole exome sequencing were used for molecular diagnosis. Disease-causing variants were identified in 44 of 173 (25.43%) patients. The clinical phenotype of these 44 patients was mostly related to infection susceptibility (63.64%). An enrichment of immune dysregulation diseases was found when cohorts with molecular diagnosis were compared to those without. Immune dysregulation disorders, group 4 from the International Union of Immunological Societies Expert Committee (IUIS), were the most prevalent among these adult patients. Immune dysregulation as a new item in the Jeffrey Model Foundation warning signs for adults significantly increases the sensitivity for the identification of patients with an IEI-producing molecular defect.

Keywords: Autoimmune lymphoproliferative syndrome (ALPS); Jeffrey model foundation warning signs; NGS; autoimmunity; germline variants; human inborn errors of immunity (IEI); immune dysregulation; infections; lymphoproliferation; primary immune regulatory disorders (PIRD); somatic variants.

Fig. 1

A Forty-four patients (25.43%) were molecularly diagnosed (w_MolDx) and 129 patients (74.57%) were not diagnosed (wo_MolDx) in the IEI adult cohort (n = 173 patients). B Positive genetic diagnosis as a function of age. C Clinical features of adult patient w_MolDx. D Clinical features of adult patient wo_MolDx. E Percentage and number of patients with immune dysregulation according to molecular diagnosis (w_MolDx and wo_MolDx) (p < 0.05). F Distribution of diagnosed patients according to the IUIS classification

Fig. 2

A Methods for genetic screening of 48 variants described in 44 patients. B Reported vs. no reported molecular variants. C Distribution of zygosity for the patients for whom variants were identified in the IEI cohort (n = 44 patients). D Distribution of patients depending on the type of molecular variant (germline or somatic). E Percentage of HSCT patients and without HSCT (wo_HSCT)