Genetic diagnosis of autoinflammatory disease patients using clinical exome sequencing

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.
This study was funded by grants SAF2012-35025 and SAF2015-68472-C2-2-R from the Ministerio de Economía y Competitividad (Spain) and FEDER (EU) to FC; RTI2018-096824-B-C22 grant from the Spanish Ministry of Science, Innovation and Universities co-financed by ERDF (FC), by Direcció General de Recerca, Generalitat de Catalunya (2014SGR-866 and 2017SGR-702) to FC, the CERCA Programme, Generalitat de Catalunya (JIA), SAF2015-68472-C2-1-R grant from the Spanish Ministry of Economy and Competitiveness co-financed by European Regional Development Fund (ERDF) (JIA), RTI2018-096824-B-C21 grant from the Spanish Ministry of Science, Innovation and Universities co-financed by ERDF (JIA), and AC15/00027 grant from the Instituto de Salud Carlos III, Transnational Research Projects on Rare Diseases (JIA). LBM is supported by a Formació de personal Investigador fellowship from Generalitat de Catalunya (2018_FI_B00072). MSM is supported by the María de Maetzu Programme (MDM-2014-0370-16-3).