Abstract
X-linked hyper-immunoglobulin M (X-HIGM) syndrome and autosomal recessive hyper-immunoglobulin E syndrome (HIES) are rare inborn errors of immunity characterized by recurrent infections due to immune system impairment. In this study, we identified a novel hemizygous CD40 ligand (CD40L) mutation and compound heterozygous dedicator of cytokinesis-8 (DOCK8) mutations in two Han Chinese families with X-HIGM and HIES, respectively. We aimed to investigate the association between their genotypes and phenotypes. Genomic DNA was extracted from peripheral blood samples obtained from the families. Whole exome sequencing and Sanger sequencing were performed to identify and verify pathogenic variants in the two families. Clinical analyses of the probands were also performed. A novel hemizygous mutation of CD40L in exon 2 (c.257delA) was identified in the first proband, resulting in the substitution of glycine with glutamic acid at codon 86 of the protein. This leads to premature termination of translation at downstream codon 9 (p.E86Gfs*9). Sanger sequencing confirmed that the variant was inherited from the mother. The second proband carried two novel compound heterozygous mutations in DOCK8: one at exon 14 (c.1546C > G) inherited from the father, and the other at intron 41 (c.5355 + 6C > T; splicing) inherited from the mother. This study enhances our understanding of the pathogenetic mutation spectrum of CD40L and DOCK8 genes, facilitating the prenatal diagnosis of X-HIGM and HIES and enabling timely treatment of patients.
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The data supporting the findings of this study can be obtained from the corresponding authors upon reasonable request.
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We are grateful to all the research subjects, their families, and those who provided sincere help to our study. The authors thank Editage (www.editage.cn) for English language editing.
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This work was supported by the National Key Research and Development Program (grant number 2016YFC1000306) and the National Natural Science Foundation of China (NSFC) (81371499).
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Shiguo Liu and Niyan Qu conceived and designed the experiments. Mingzhen Guo and Yuanxuan Ma drafted the initial manuscript. Xiuxiang Liu participated in the collection of specimens. Wenmiao Liu and Fengqi Wang completed the experiment. Kangxi Cai was involved in the analysis of the experimental data. Shiguo Liu revised the first draft of the paper.
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Guo, M., Ma, Y., Cai, K. et al. A novel hemizygous CD40L mutation of X-linked hyper IgM syndromes and compound heterozygous DOCK8 mutations of hyper IgE syndromes in two Chinese families. Immunogenetics (2024). https://doi.org/10.1007/s00251-024-01340-0
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DOI: https://doi.org/10.1007/s00251-024-01340-0