Multi-OMICS analyses unveil STAT1 as a potential modifier gene in mevalonate kinase deficiency

Abstract

ObjectivesThe objective of the present study was to explain why two siblings carrying both the same homozygous pathogenic mutation for the autoinflammatory disease hyper IgD syndrome, show opposite phenotypes, that is, the first being asymptomatic, the second presenting all classical characteristics of the disease.MethodsWhere single omics (mainly exome) analysis fails to identify culprit genes/mutations in human complex diseases, multiomics analyses may provide solutions, although this has been seldom used in a clinical setting. Here we combine exome, transcriptome and proteome analyses to decipher at a molecular level, the phenotypic differences between the two siblings.ResultsThis multiomics approach led to the identification of a single gene—STAT1—which harboured a rare missense variant and showed a significant overexpression of both mRNA and protein in the symptomatic versus the asymptomatic sister. This variant was shown to be of gain of function nature, involved in an increased activation of the Janus kinase/signal transducer and activator of transcription signalling (JAK/STAT) pathway, known to play a critical role in inflammatory diseases and for which specific biotherapies presently exist. Pathway analyses 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.ConclusionsThis study demonstrates the power of a multiomics approach to uncover potential clinically actionable targets for a personalised therapy. In more general terms, we provide a proteogenomics analysis pipeline that takes advantage of subject-specific genomic and transcriptomic information to improve protein identification and hence advance individualised medicine.

A scoping review and proposed workflow for multi-omic rare disease research

“…• To explain polarised phenotypic heterogeneity in siblings with the same pathogenic mutation [111].…”

“…The spectrum of clinical presentations includes hyperimmunoglobulinemia D syndrome, periodic fever syndrome and mevalonic aciduria [155]. This study conducted WES, RNA-Seq and differential protein analysis in a case study of two sisters presenting with polarised phenotypic heterogeneity where they both harboured a known driver homozygous mutation in MVK but only one sibling presented with disease symptoms [111]. Their integrative multi-omic analysis identified a rare mutation in the modifier gene STAT1 resulting in upregulated mRNA AND protein expression, likely responsible for the phenotype in the affected sister.…”

Periodic fever syndromes and the autoinflammatory diseases (AIDs)

“…Recently, a gain of function mutation of signal transducer and activator of transcription signaling 1 (STAT1) gene (p.R241Q) discovered thanks to this mutliomics approach has been found to play a critical role into disease phenotype expression. Indeed two sisters carrying the same homozygous V377I mutation showed asymptomatic and symptomatic clinical phenotype respectively due to the presence of STAT1 mutation in the symptomatic patient [ 56 ]. This finding might have repercussions on the treatment since the janus kinase (JAK)/STAT1 pathway can be targeted by several drugs.…”

Identifying Genetic Modifiers in the Age of Exome: Current Considerations

“…Escobar et al added stratification based on physical examination, decreasing the proportion of infants selected for treatment to 4% (116 uninfected infants treated for each treated case of EOS) while increasing case ascertainment to 60%. 11 To facilitate clinical adoption, Kuzniewicz et al placed the regression model into an algorithmic framework that includes categorical recommendations for "serious consideration" of empiric treatment for all newborn infants with clinical signs of illness and evaluation of "vital signs every 4 hours" for infants at intermediate risk. 12 The resulting Neonatal Early-Onset Sepsis Calculator has been made available by the Kaiser Permanente Division of Research as an online tool, 13 and its clinical performance has been described.…”

“…This is problematic, because the investigators are searching for modifier loci which may be the result of common genetic variants 7,8 in regulatory rather than protein coding genes. [9][10][11] The investigators ignore the contribution of common variation. For Mendelian traits, the expectation that causal variants be rare, as delineated by the American College of Medical Genetics and Genomics 2015 guidelines, 12 is consistent with population genetic principles as genotypic frequencies inform phenotypic frequencies.…”