Autoinflammatory Diseases: Germline vs. Somatic Mosaic Variations
Résumé
Background/Objectives:
The study primarily investigates somatic mosaic variations within systemic autoinflammatory
diseases (SAID) genes and their correlation with disease phenotypes, specifically focusing
on variations in NLRP3 and TNFRSF1A leading to NLRP3-AIDs and TRAPS (Tumor
necrosis factor-Receptor-Associated Periodic Syndrome) respectively.
Methods:
From 2018 to 2023, deep-targeted NGS was used to analyze the leukocyte DNAs of 800
patients using a SAID gene panel. All mosaic variations in SAID genes from PubMed and
Infevers databases were reviewed.
Results:
In NLRP3, 9 mosaic variations were identified in 12 independent patients, along with 10
germline variations in 10 patients. The literature reports 34 mosaic and 88 germline NLRP3
variations.
Phenotype: genotype correlations suggest that NLRP3 variations found only somatically may
be incompatible with life if present germinally, while variations found only in germinal state
could be asymptomatic in mosaic state.
In TNFRSF1A, two mosaic variations were found in three patients. The literature reports only
three other mosaic variations. No obvious difference in disease severity between germline
and mosaic variations has been observed.
Very few mosaic variations have been reported in the literature in other SAID genes: NLRC4
(n=4), STING1 (n=2), NOD2 (n=2), and JAK1 (n=1), precluding any genotype: phenotype
correlation studies.
Most of mosaic variations identified in SAID genes were found to be widely distributed across
different tissues.
Conclusion:
The study underscores the high frequency of mosaic variations in NLRP3-AIDs and
emphasizes the symptomatic nature of mosaic variations, even at very low allele frequencies
(below 5%), potentially leading to false-negative diagnostic tests without deep sequencing
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