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<p>Autoinflammatory diseases (AIDs) are a group of disorders caused by a dysregulation of the innate immune system, among which inflammasomopathies are characterized by recurrent episodes of fever associated with systemic inflammation and organ involvement. Gain-of-function variants in the inflammasome-related gene <i>NLRC4</i> underlie severe phenotypes such as infantile enterocolitis and macrophage activation syndrome (MAS). While most <i>NLRC4</i> variants are germline, somatic mosaic variants remain rare, with only three documented cases. In this study, following a targeted deep next-generation sequencing approach, we identified a <i>NLRC4</i> variant —c.398C&gt;T p.(Thr133Ile)— in a somatic mosaic state (variant allele fraction of 5%) in a 28-year-old patient with recurrent episodes of systemic inflammation without MAS. Functional analyses revealed that this variant, as well as two previously reported <i>NLRC4</i> mosaic variants, resulted in a gain-of-function effect on NLRC4 inflammasome and NF-κB pathway activation. While relying on data from all reported patients with <i>NLRC4</i> mosaic variants, we also showed that all mosaic variants cluster near the NLRC4 adenosine-diphosphate binding site and that patients with high levels of mosaicism had earlier and more severe symptoms than those with lower mosaicism levels. Overall, our findings, which unveil a correlation between the percentage of mosaicism and the age of onset and severity of the disease, underline the need to recognize the full spectrum of NLRC4-AIDs, which can often be underdiagnosed, particularly in patients with low mosaicism levels. Such a diagnosis is, however, essential, as targeted treatments —such as anti-IL-1 therapies, which proved highly effective for our patient— can significantly improve patient outcomes.</p>

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Somatic Mosaic NLRC4 Variants in Autoinflammatory Diseases: Functional Characterization and Correlation of Mosaicism Levels with Disease Age of Onset and Severity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月8日

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  • Farah Diab,
  • Camille Louvrier,
  • Marc Fabre,
  • Christine Lin,
  • Mira Rabbaa,
  • Eman Assrawi,
  • Aphrodite Daskalopoulou,
  • Rahma Mani,
  • Florence Dastot Le Moal,
  • William Piterboth,
  • Marie Legendre,
  • Serge Amselem,
  • Sonia Athina Karabina,
  • Irina Giurgea

摘要

Autoinflammatory diseases (AIDs) are a group of disorders caused by a dysregulation of the innate immune system, among which inflammasomopathies are characterized by recurrent episodes of fever associated with systemic inflammation and organ involvement. Gain-of-function variants in the inflammasome-related gene NLRC4 underlie severe phenotypes such as infantile enterocolitis and macrophage activation syndrome (MAS). While most NLRC4 variants are germline, somatic mosaic variants remain rare, with only three documented cases. In this study, following a targeted deep next-generation sequencing approach, we identified a NLRC4 variant —c.398C>T p.(Thr133Ile)— in a somatic mosaic state (variant allele fraction of 5%) in a 28-year-old patient with recurrent episodes of systemic inflammation without MAS. Functional analyses revealed that this variant, as well as two previously reported NLRC4 mosaic variants, resulted in a gain-of-function effect on NLRC4 inflammasome and NF-κB pathway activation. While relying on data from all reported patients with NLRC4 mosaic variants, we also showed that all mosaic variants cluster near the NLRC4 adenosine-diphosphate binding site and that patients with high levels of mosaicism had earlier and more severe symptoms than those with lower mosaicism levels. Overall, our findings, which unveil a correlation between the percentage of mosaicism and the age of onset and severity of the disease, underline the need to recognize the full spectrum of NLRC4-AIDs, which can often be underdiagnosed, particularly in patients with low mosaicism levels. Such a diagnosis is, however, essential, as targeted treatments —such as anti-IL-1 therapies, which proved highly effective for our patient— can significantly improve patient outcomes.