A synonymous variant in IL10RA affects RNA splicing in paediatric patients with refractory inflammatory bowel disease

Abstract

Interleukin-10 receptor [IL10R] mutations are associated with severe childhood inflammatory bowel disease [IBD]. Two unrelated patients who died of very early-onset severe IBD and sepsis were identified as harbouring the same compound heterozygous mutations in IL10RA [p.R101W; p.T179T]. A third patient was found to be homozygous for p.T179T. The missense change of p.R101W has been reported. The synonymous change of p.T179T, with a minor allele frequency of 0.035% in the population, was novel. The p.T179T mutation was located before the 5' splice donor site, leading to exon skipping and out-of-frame fusion of exons 3 and 5, causing altered STAT3 phosphorylation in IL10-induced peripheral blood mononuclear cells. The patient developed colitis at 6 years of age, the oldest reported age of onset among patients with IL10RA mutations, and did not suffer from perianal disease. We report three paediatric patients with a rare, synonymous p.T179T variant causing a splicing error in IL10RA.