Genetic testing in autoinflammatory diseases - past, current and future perspectives

Autoinflammatory diseases (AID) are a group of rare monogenic illnesses, leading to uncontrolled activation of the innate immune system and presenting with recurrent flares of systemic and localized inflammation. Diagnosis is confirmed by the detection of a class IV or class V gene variant in an AID-related gene and improvements in sequencing techniques have enabled the discovery of new entities. The aim of our study is to explore the diagnostic yield of evolving genetic testing methods for AID and to determine whether increasing gene panels generate a higher diagnostic rate.

Retrospective study of 2620 patients that underwent sequencing for a clinical suspicion of AID in Belgium, between January 2015 and December 2020. Sequencing was performed through a 10-gene panel between 2015 and 2017, a 25-gene panel between 2018 and 2020 and mendeliome technology with a 66- and a 502- in silico gene panel in 2020.

The rate of genetic diagnoses increased along with the expansion of the gene panel with a diagnostic yield of 15% with 10 genes, 16% with 25 genes and 23% with 502 genes.

Our study is the first nationwide study for autoinflammatory genetic testing and the first use of mendeliome technology for AID diagnosis. Although we confirmed that the bigger the gene panel, the higher the diagnostic rate, this technology generated inevitably a higher financial and human cost although the majority of diagnoses remained amongst the four original hereditary recurrent fevers (HRFs).