Role of Skewed X-Chromosome Inactivation in Common Variable Immunodeficiency

In this study, we aimed to assess the role of skewed X-chromosome inactivation (XCI) in CVID. Within our cohort of 131 genetically analyzed CVID patients, we selected female patients with rare variants in CVID-associated genes located on the X-chromosome. Four patients harboring heterozygous variants inBTK (n = 2),CD40LG (n = 1), andIKBKG (n = 1) were included in the study. We assessed XCI status using the HUMARA assay and an NGS-based method to quantify the expression of the 2 alleles in mRNA. Three of the 4 patients (75%) exhibited skewed XCI, and the mutated allele was predominantly expressed in all cases. Patient 1 harbored a hypomorphic variant inBTK (p.Tyr418His), patient 3 had a pathogenic variant inCD40LG (c.288+1G>A), and patient 4 had a hypomorphic variant inIKBKG (p.Glu57Lys) and a heterozygous splice variant inTNFRSF13B (TACI) (c.61+2T>A). Overall, the analysis of our cohort suggests that CVID in a small proportion of females (1.6% in our cohort) is caused by skewed XCI and highly penetrant gene variants on the X-chromosome. Additionally, skewed XCI may contribute to polygenic effects (3.3% in our cohort). These results indicate that skewed XCI may represent another piece in the complex puzzle of CVID genetics.
Source: Journal of Clinical Immunology - Category: Allergy & Immunology Source Type: research