A Heterozygous IFIH1-Δ14 Polymorphism that Causes Severe Systemic Inflammatory Reactions Resembling Hemophagocytic...

Type I interferon signaling is central to antiviral innate immunity, and disruption of this pathway may contribute to unusually severe illness during otherwise common viral infections in children. We report a previously healthy 12-month-old girl who presented with a fever for two weeks, followed by a generalized skin rash. She then subsequently developed a persistent fever, pancytopenia, splenomegaly, elevated soluble IL-2 receptor, and hypofibrinogenemia, fulfilling diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH). Because an underlying immune disorder was suspected, targeted panel sequencing was performed, followed by Sanger confirmation and RNA transcript analysis; this identified a heterozygous IFIH1 splice-site variant (NM_022168.4:c.2807+1G>A (rs35732034)). Reverse transcription-polymerase chain reaction and transcript sequencing demonstrated exon 14 skipping (Δ14) in patient RNA, providing direct confirmation of the predicted splicing abnormality and aligning with the prior report by Asgari et al. regarding this same variant in children with severe viral illness. Although these findings support the biological relevance of the variant in this clinical setting, they do not establish a causal relationship or indicate that the variant was the sole cause of the inflammatory syndrome. As a single case report, this observation should therefore be interpreted cautiously; however, it suggests that IFIH1 abnormalities may be associated with infection-related hyperinflammation or an HLH-like presentation in some patients and highlights the value of RNA-based validation when interpreting candidate splice-site variants in innate immune genes.