Identification of genetic sequence variations associated with the pathogenesis of X-linked hyper-IgM syndrome

Abstract Background: X-Linked Hyper-IgM Syndrome (X-HIGM) is a rare genetic primary immunodeficiency disease caused by mutations of the CD40 ligand gene (CD40LG). It is characterized by normal or elevated levels of IgM and markedly decreased serum IgG, IgA, and IgE levels. Patients with this syndrome are often prone to infections. Environmental and genetic (especially genetic mutation) factors may play an important role in etiology, development, and pathogenesis of X-HIGM. Methods: DNA from a male child diagnosed as having X-HIGM and DNA from his healthy mother were used for whole-exome (next-generation) sequencing and targeted gene sequencing. The results were analyzed using Exome Aggregation Consortium data and the Genome Aggregation Database and were further validated using Sanger sequencing. Results: Next-generation sequencing results indicated that the CD40LG gene in the child had a p.R203I variant. In addition, his mother was a carrier, suggesting that the child’s p.R203I homozygous mutation was inherited from his mother. The functional prediction scores from SIFT, MetaSVM, and FATHMM software indicated that this genetic variant may be harmful. Conclusions: Single variations in many exons of the CD40LG gene can lead to X-HIGM. Although the pathogenicity of the variant identified in the present study has not been previously reported, prediction software found that it would be harmful. Thus, CD40LG may be related to this genetic disease. Despite these limitations, our findings provided insight into X-HIGM pathogenesis and suggested a potential target for therapeutic drug development.