Clin Immunol. 2024 Oct 20. pii: S1521-6616(24)00493-5. [Epub ahead of print] 110384
Fatma Betul Oktelik,
Muyun Wang,
Sevgi Keles,
Hatice Eke Gungor,
Murat Cansever,
Salim Can,
Elif Karakoc-Aydiner,
Safa Baris,
Klaus Schmitz-Abe,
Mehdi Benamar,
Talal A Chatila.
Dedicator of cytokinesis 8 (DOCK8) deficiency underlies the majority of cases of patients with autosomal recessive form of the hyper-immunoglobulin E syndrome (HIES). Most DOCK8 mutations involve deletions and splice junction mutations that abrogate protein expression. However, a few patients whose presentation is reminiscent of DOCK8 deficiency have no identifiable mutations. Using Whole Exome Sequencing (WES), we identified a deep intronic homozygous DOCK8 variant located in intron 36 (c.4626 + 76 A > G) in two unrelated patients with features of HIES that resulted in an in-frame 75 base pair intronic sequence insertion in DOCK8 cDNA, resulting in a premature stop codon (p.S1542ins6Ter). This variant resulted in variable decrease in DOCK8 expression that was associated with impaired T cell receptor-triggered actin polymerization, decreased IL-6-induced STAT3 phosphorylation, reduced expression of the Th17 cell markers CCR6 and IL-17, and higher frequencies of GATA3+ T cells indicative of Th2 skewing. Our approach extends the reach of WES in identifying disease-related intronic variants. It highlights the role of non-coding mutations in immunodeficiency disorders, including DOCK8 deficiency, and emphasizes the need to explore these mutations in unexplained inborn errors of immunity.
Keywords: DOCK8; Hyper-immunoglobulin E syndrome (HIES); Inborn errors of immunity; Intronic mutation; Whole exome sequencing (WES)