Heterogeneous phenotype of a Chinese Familial WHIM syndrome with CXCR4V340fs gain-of-function mutation.

Background: WHIM syndrome is a rare, autosomal dominant inborn error of immunity characterized by warts, hypogammaglobulinemia, infection, and myelokathexis. It is caused mainly by heterozygous mutations at the C-terminus of the C-X-C chemokine receptor type 4 (CXCR4) gene.

Methods: We described the detailed clinical, genetic, immunological and treatment characteristic of four WHIM patients from a single Chinese family.

Results: Here, we report four patients from a family carrying a variant of CXCR4 (c.1016_1017dupCT), which introduces a frameshift at codon V340, resulting in an extension of 14 amino acids (p.V340L fs*27). We provide and in-depth analysis of their clinical, genetic, immunological and treatment characteristic, noting that these patients exhibited an atypical clinical phenotype when compared to reported CXCR4^R334X patients. Additionally, the frameshift variant CXCR4^V340fs led to impaired receptor downregulation in patients' PBMCs, and in HEK293T cells transfected with the variant plasmids.

Conclusions: Our study provided detailed clinical features of four CXCR4^V340fs WHIM patients from one Chinese family who presented atypical phenotype and enrich the spectrum of WHIM syndrome.