Case report: Novel compound heterozygous IL1RN mutations as the likely cause of a lethal form of deficiency of interleukin-1 receptor antagonist

• DOI: 10.3389/fimmu.2024.1381447
• Publication Date: 2024-04-05T04:28:15Z
• Authors: Elena Urbaneja; Nuria Bonet; Manuel Solis-Moruno; Anna Mensa-Vilaro; Iñaki Ortiz de La...; Marc Tormo; Rocio Lara; Susana Plaza; Virginia Fabregat; Jordi Yagüe; Ferran Casals; Juan I. Arostegui
• Keywords: Sanger sequencing; Heterozygote advantage; Compound heterozygosity; genomic DNA; Loss function

Undiagnosed monogenic diseases represent a challenging group of human conditions highly suspicious to have genetic origin, but without conclusive evidences about it. We identified two brothers born prematurely from non-consanguineous healthy couple, with neonatal-onset, chronic disease characterized by severe skin and bone inflammatory manifestations fatal outcome in infancy. conducted DNA mRNA analyses the patients’ relatives identify cause disease. were performed both Sanger next-generation sequencing, which novel heterozygous IL1RN variants: intronic c.318 + 2T>G variant father ≈2,600-bp intragenic deletion mother. production was markedly decreased progenitors when compared subjects. The sequencing each parent novel, truncated transcripts. Additional experiments revealed perfect intrafamilial phenotype–genotype segregation following an autosomal recessive inheritance pattern. shown here supported for presence loss-of-function (LoF) pathogenic variants analyzed family. Biallelic LoF at gene deficiency interleukin-1 receptor antagonist (DIRA), autoinflammatory marked similarities patients described here. Despite non-availability samples representing main limitation this study, collected strongly suggest that suffered lethal form DIRA likely due compound genotype , thus providing reliable diagnosis based on integration old medical information currently obtained data.