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The following is a summary of “Splice site and de novo variants can cause PLCG2-associated immune dysregulation with cold urticaria (PLAID-CU),” published in the December 2024 issue of Allergy and Immunology by Chou et al. 

Phospholipase Cγ2 (PLCγ2) is a key signaling molecule in hematopoietic cells. Variants of PLCG2 lead to PLCγ2-associated immune dysregulation (PLAID), with cold urticaria (PLAID-CU) caused by in-frame deletions that become active at low temperatures. 

Researchers conducted a retrospective study to identify genetic lesions causing PLAID by combining RNA sequencing of full-length PLCG2 with whole genome sequencing. 

They studied 9 antibody-deficient probands, 2 patients with PLAID-CU, and 3 healthy subjects. Illumina sequencing of PLCG2 cDNA from peripheral blood mononuclear cell RNA and whole genome sequencing identified genetic lesions. Novel transcripts were overexpressed in PLCG2-deficient DT40 cells, and ERK phosphorylation was measured by flow cytometry with and without BCR crosslinking. 

The results showed that 2 probands expressed novel PLCG2 transcripts with in-frame deletions. Proband 1, lacking exons 18-19, had a splice site mutation in intron 19. Proband 2, lacking exons 19-22, carried a 14kb de novo deletion. DT40 cells overexpressing exon 18-19 or exon 19-22 deletions failed to phosphorylate ERK upon BCR crosslinking. 

They concluded that in addition to autosomal dominant deletions, de novo deletions and splice site mutations of PLCG2 contributed to PLAID-CU. These genetic lesions were identifiable through cDNA-based sequencing. 

Source: jacionline.org/article/S0091-6749(24)01287-9/abstract