Genetic diagnosis of autoinflammatory disease patients using clinical exome sequencing

Eur J Med Genet. 2020 May;63(5):103920. doi: 10.1016/j.ejmg.2020.103920. Epub 2020 Mar 25.


Autoinflammatory diseases comprise a wide range of syndromes caused by dysregulation of the innate immune response. They are difficult to diagnose due to their phenotypic heterogeneity and variable expressivity. Thus, the genetic origin of the disease remains undetermined for an important proportion of patients. We aim to identify causal genetic variants in patients with suspected autoinflammatory disease and to test the advantages and limitations of the clinical exome gene panels for molecular diagnosis. Twenty-two unrelated patients with clinical features of autoinflammatory diseases were analyzed using clinical exome sequencing (~4800 genes), followed by bioinformatic analyses to detect likely pathogenic variants. By integrating genetic and clinical information, we found a likely causative heterozygous genetic variant in NFKBIA (p.D31N) in a North-African patient with a clinical picture resembling the deficiency of interleukin-1 receptor antagonist, and a heterozygous variant in DNASE2 (p.G322D) in a Spanish patient with a suspected lupus-like monogenic disorder. We also found variants likely to increase the susceptibility to autoinflammatory diseases in three additional Spanish patients: one with an initial diagnosis of juvenile idiopathic arthritis who carries two heterozygous UNC13D variants (p.R727Q and p.A59T), and two with early-onset inflammatory bowel disease harbouring NOD2 variants (p.L221R and p.A728V respectively). Our results show a similar proportion of molecular diagnosis to other studies using whole exome or targeted resequencing in primary immunodeficiencies. Thus, despite its main limitation of not including all candidate genes, clinical exome targeted sequencing can be an appropriate approach to detect likely causative variants in autoinflammatory diseases.

Keywords: Autoinflammatory diseases; Clinical exome; Gene panels; Primary immunodeficiency; Targeted sequencing.

MeSH terms

  • Autoimmune Diseases / genetics*
  • Autoimmune Diseases / pathology
  • Deoxyribonucleases / genetics
  • Exome Sequencing / methods*
  • Exome Sequencing / standards
  • Female
  • Genetic Testing / methods*
  • Genetic Testing / standards
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Mutation
  • NF-KappaB Inhibitor alpha / genetics
  • Nod2 Signaling Adaptor Protein / genetics


  • Membrane Proteins
  • NFKBIA protein, human
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • UNC13D protein, human
  • NF-KappaB Inhibitor alpha
  • Deoxyribonucleases
  • DNASE2 protein, human