Updated publication reference for PubMed record(s): 30030262. The aim of this study was to understand why two siblings carrying both the same homozygous causal mutation for the auto-inflammatory disease hyper IgD show opposite phenotypes, i.e. the first being asymptomatic, the second presenting all classical characteristics of the disease. As compared to studies of a single omics type, the multi-omics approach becomes a method of choice to resolve complex traits. Here we combined exome, proteome and transcriptome analysis in the two siblings and identified a single gene - STAT1 - harboring a rare missense variant and showing mRNA and protein abundances significantly more important in the symptomatic than the asymptomatic sister. This mutation was shown to be a gain of function mutation involved in an increased activation of the JAK/STAT pathway which is known to play a critical role in inflammatory diseases and for which specific bio-therapies exist. Pathway analysis based on information from differentially expressed transcripts and proteins confirmed the central role of STAT1 in the proposed regulatory network leading to an increased inflammatory phenotype in the symptomatic sibling. In addition, we provide a proteogenomics analysis pipeline that takes advantage of subject-specific genomic and transcriptomic information to improve protein identifications. In conclusion, this study demonstrates the power of a multi-omics approach to uncover potentially clinically actionable targets for a personalized therapy.