OTULIN Haploinsufficiency Caused by a Novel Splice Acceptor Variant

Inborn errors of immunity (IEIs) represent a diverse group of genetic disorders that compromise immune function, leading to susceptibility to infections and immune dysregulation. Biallelic and heterozygous loss-of-function variants in OTULIN have recently been found to cause IEIs. OTULIN is an important regulator of inflammatory signaling through its role as a deubiquitinating enzyme of linear ubiquitin chains. While complete deficiency of OTULIN causes a severe and early-onset autoinflammatory syndrome, heterozygous loss-of-function has been associated with a variably penetrant phenotype of environmental and infection-triggered inflammation. We report a 43-year-old male with recurrent soft tissue inflammation, osteomyelitis, and inflammatory bowel disease. His childhood was characterized by frequent episodes of severe soft tissue inflammation since 2 months of age, triggered by minor trauma, immunizations, and infections, followed by a diagnosis of inflammatory bowel disease in adolescence. The episodes of soft tissue inflammation have persisted into adulthood, though they have lessened in frequency and respond to corticosteroids. Whole-exome sequencing revealed a heterozygous OTULIN variant (NM_138348.6: c.788G>A, p.(R263Q)). Surprisingly, in silico analysis using the splice site prediction tool SpliceAI indicated that the variant would create a novel splice acceptor site 2 base pairs from the variant (delta score 0.91). This was validated by RT-PCR amplification of cDNA derived from patient whole blood RNA. While control mRNA demonstrated a single band at the expected molecular size, the patient mRNA showed one band at the expected size with additional amplified bands, in keeping with alternative splicing. Sanger sequencing demonstrated that the full-length band contained wild-type cDNA, and the second largest band contained cDNA with a partial deletion of exon 6. This study further expands on the phenotypic characterization of OTULIN haploinsufficiency and highlights the importance of considering monogenic immune disorders in both pediatric and adult patients with unexplained severe inflammation.