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

Front Immunol. 2024 Apr 5:15:1381447. doi: 10.3389/fimmu.2024.1381447. eCollection 2024.

Abstract

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

Keywords: autoinflammatory diseases (AID); case report; interleukin-1; interleukin-1 receptor antagonist (IL-1 ra); whole-genome sequencing (WGS).

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Fatal Outcome
  • Female
  • Hereditary Autoinflammatory Diseases / diagnosis
  • Hereditary Autoinflammatory Diseases / genetics
  • Heterozygote*
  • Humans
  • Infant
  • Infant, Newborn
  • Interleukin 1 Receptor Antagonist Protein* / genetics
  • Male
  • Mutation*
  • Pedigree*
  • Phenotype

Substances

  • Interleukin 1 Receptor Antagonist Protein
  • IL1RN protein, human

Supplementary concepts

  • Deficiency of interleukin-1 receptor antagonist

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work has been partially funded by RTI2018-096824-B-C21 (JA) and RTI2018-096824-B-C22 (FC) grants from the Spanish Ministry of Science, Innovation and Universities co-funded by Agencia Estatal de Investigación/European Regional Development Fund una manera de hacer Europa; PID2021-125106OB-C31 (JA) and PID2021-125106OB-C32 (FC) grants from the Ministerio de Ciencia e Innovación (MCIN) | Agencia Estatal de Investigación (AEI) | 10.13039/501100011033 | Fondo Europeo de Desarrollo Regional (FEDER), UE; AC21_2/00042 grant from the Instituto de Salud Carlos III co-funded by Unión Europea Next Generation EU | Mecanismo para la Recuperación y la Resiliencia (MRR) | Plan de Recuperación, Transformación y Resiliencia (PRTR); PI19/01567 grant from Instituto de Salud Carlos III (ISCIII) co-funded by the European Union (AM-V).