Exon skipping caused by a complex structural variation in SH2D1A resulted in X‐linked lymphoproliferative syndrome type 1

BACKGROUND: X‐linked lymphoproliferative syndrome type 1 (XLP1) is a rare primary immunodeficiency disorder characterized by severe immune dysregulation often after viral infection. It is caused by hemizygous mutations in the X‐linked SH2D1A gene. People with XLP1 have complex and variable phenotype manifestations as EBV‐driven severe or fulminant mononucleosis, hemophagocytic lymphohistiocytosis (EBV‐HLH), dysgammaglobulinemia, and B‐cell lymphoma. METHODS: Immunological analyses, clinical laboratory testing, and whole exome sequencing (WES) were performed to help the disease diagnosis for the patient with severe immune dysregulation. Routine and extended WES analysis pipelines were applied to explore candidates. A complex genomic structural variation in SH2D1A was detected and verified by Inverse‐PCR, Gap‐PCR, and RT‐PCR. RESULTS: Here we reported that a five‐year‐old male patient manifested with EBV‐HLH, recurrent infection by severe immune dysregulation, and successfully managed with HSCT. He finally established precise disease diagnosis as XLP1 caused by a complex genomic structural variation in SH2D1A (NC_000023.11:g. [124,350,560_124365777del; 124,365,777_124365917inv; 124,365,911_124365916del]). The mother and grandmother of the proband were confirmed to be carriers. The complex variant resulted in the exon 2 skipping and was predicted to generate a prematurely truncated protein. CONCLUSION: The complex structural variant combined with paracentric inversion and large size deletions was first reported in XLP1 cases. It is considered to be pathogenic based on the truncation of the mRNA sequence and cosegregation with the disease in three‐generation pedigree analysis. This finding has expanded the known XLP‐related mutation spectrum in Chinese patients and indicated remarkable effects on the early diagnosis and therapeutic implication using proper molecular testing techniques.