Whole exome sequencing in unclassified autoinflammatory diseases: more monogenic diseases in the pipeline?

Rheumatology (Oxford). 2021 Feb 1;60(2):607-616. doi: 10.1093/rheumatology/keaa165.


Objective: Autoinflammatory diseases (AIDs) are characterized by recurrent sterile systemic inflammation attacks. More than half of the patients remain genetically undiagnosed with next-generation sequencing panels for common AIDs. In this study, we aimed to define phenotype-genotype correlations in a cohort of unclassified AID patients via whole exome sequencing (WES).

Methods: Patients with features of AIDs were included in this study followed in the Department of Pediatric Rheumatology at Hacettepe University. They were first screened for MEFV with Sanger sequencing and then WES performed for the patients with clinically insignificant results. Pre-analysis of WES data was done by considering the 13 most common AID-related genes. Further bioinformatic analysis was performed if the patient remained genetically undiagnosed.

Results: The median age at disease onset was 1.2 years (range 0.2-16) and at the time of study recruitment was 14 years (range 3.5-17). In our cohort, WES provided a definite or probable disease-causing variant in 4 of 11 patients (36%). Heterozygous mutations for two of these genes were previously associated with neurological defects (ADAM17, TBK1), also homozygous ADAM17 mutations were observed in one family with neonatal inflammatory skin and bowel disease. Besides, two genes (LIG4, RAG1) were associated with immunodeficiency although the patients had presented with inflammatory features. Finally, for one patient, we associated a strong candidate gene (NLRC3) with autoinflammatory features.

Conclusion: WES strategy is cost-effective and provides substantial results for a selected group of undefined AID patients. Our results will contribute to the spectrum of unclassified AIDs.

Keywords: NLRC3; novel candidate gene; unclassified autoinflammatory disease; whole exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Exome Sequencing / methods*
  • Female
  • Genetic Association Studies
  • Hereditary Autoinflammatory Diseases / genetics*
  • Hereditary Autoinflammatory Diseases / metabolism
  • Humans
  • Infant
  • Male
  • Mutation*
  • Phenotype
  • Pyrin / genetics*
  • Pyrin / metabolism
  • Sequence Analysis, DNA


  • MEFV protein, human
  • Pyrin