A novel de novo NLRC4 mutation reinforces the likely pathogenicity of specific LRR domain mutation
Document Type
Article
Publication Date
2-1-2020
Abstract
Autoinflammatory disorders are characterized by dysregulated innate immune response, resulting in recurrent uncontrolled systemic inflammation and fever. Gain-of-function mutations in NLRC4 have been described to cause a range of autoinflammatory disorders. We report a twelve-year-old Malay girl with recurrent fever, skin erythema, and inflammatory arthritis. Whole exome sequencing and subsequent bidirectional Sanger sequencing identified a heterozygous missense mutation in NLRC4 (NM_001199138: c.1970A > T). This variant was predicted to be damaging in silico, was absent in public and local databases and occurred in a highly conserved residue in the leucine-rich repeat (LRR) domain. Cytokine analysis showed extremely high serum IL-18 and IL-18/CXCL9 ratio, consistent with other NLRC4-MAS patients. In summary, we identified the first patient with a novel de novo heterozygous NLRC4 gene mutation contributing to autoinflammatory disease in Malaysia. Our findings reinforce the likely pathogenicity of specific LRR domain mutations in NLRC4 and expand the clinical spectrum of NLRC4 mutations.
Keywords
Autoinflammatory disease, NLRC4, Inflammasome, Whole exome sequencing
Divisions
InstituteofBiologicalSciences
Funders
Ministry of Health, Malaysia [Grant No: NMRR-16-892-31023],National Institute of Allergy and Infectious Diseases [Grant No: K22AI123366]
Publication Title
CLINICAL IMMUNOLOGY
Volume
211
Publisher
Academic Press Inc Elsevier Science
Publisher Location
525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA