Contribution of genetic variants associated with primary immunodeficiencies to childhood-onset systemic lupus erythematous

Abstract

A dysregulated immune response is a hallmark of autoimmune disorders. Evidence suggests that systemic autoimmune diseases and primary immunodeficiency disorders (PID) may be similar diseases with different clinical phenotypes. This study aimed to investigate the burden of PID-associated genetic variants in patients with childhood-onset systemic lupus erythematosus (cSLE). We enrolled 118 cSLE patients regularly followed at Chang Gung Memorial Hospital. Targeted next-generation sequencing identified PID genetic variants in patients versus 1,475 unrelated healthy individuals that were further filtered by allelic frequency and various functional scores. Customized immune assays tested the functions of the identified variants. Upon filtration, 36 (30.5%) patients harbored rare variants in PID-associated genes predicted to be damaging. One homozygous TREX1 (c.294dupA) mutation and four heterozygous variants with possible dominant PID traits, including BCL11B (c.G1040T), NFKB1 (c.T695G), and NFKB2 (c.G1210A, c.G1651A), were discovered. With recessive traits, variants were found across all PID types; one-fifth involved phagocyte number or function defects. Predicted pathogenic PID variants were more predominant in those with a family history of lupus regardless of infection susceptibility. Moreover, mutational loads were greater among cSLE patients than controls despite sex or age at disease onset. While greater mutational loads were observed among cSLE patients with peri-pubertal disease onset, no significant difference in sex or phenotype were noted among cSLE patients. Our findings suggest that cSLE is mostly not monogenic. Gene-specific analysis and mutational load investigations suggested that rare and predicted damaging variants in PID-related genes potentially contribute to cSLE susceptibility.