Systemic AutoInflammatory Diseases (SAID) are a growing number of monogenic and multifactorial conditions secondary to deregulation of mechanisms controlling innate immune responses and are characterized by sterile inflammation. Originally these disorders were limited to a handful of rare monogenic diseases (recurrent fevers). Thanks to the great improvement in genetic diagnostic techniques, the number of known associated genes and associated autoinflammatory phenotypes has have dramatically expanded Depending on the pattern of inheritance, the identification of one or two mutations with a known pathogenic impact and high penetrance represents an essential final step for the diagnosis of SAID. However, in a considerable proportion of cases (70-80%) molecular analysis is unable to provide diagnostic confirmation (i.e. presence of a single mutation in autosomal recessive disorders, low-penetrance mutations, functional polymorphisms or novel variants of unknown functional impact). This is important because a delay in a proper diagnosis, further delay timely treatments leading to irreversible organ damage. The Next Generation Sequencing (NGS) approach has proven to be a successful strategy for inducing a marked acceleration in rare disease gene discovery, improving clinical diagnosis, providing insight into biological mechanisms, and increasing therapeutic opportunities. Indeed, NGS represents a potential revolutionary diagnostic tool for genetic conditions, allowing the simultaneous analysis of different genes associated to a given group of inherited disorders. Moreover, NGS allows the detection of somatic mosaicism, as demonstrated in patients presenting a typical clinical phenotype, but are negative for germ-line mutations. Such NGS could present an approach to enables a definitive diagnosis in some patients with monogenic SAID, but in other cases the results can be inconclusive or even misleading. Therefore, the definitive diagnosis and classification of inherited SAID should rely on the careful interpretation of results derived from several complementary molecular analyses, in the light of the clinical phenotype. So far, formal diagnostic criteria have been developed for a few SAID, but their accuracy has not been confirmed in different ages and populations. In spite of our increasing understanding of the molecular mechanisms of SAID, there is still a large number of individuals with a clinical diagnosis of SAID and but without mutations in known disease causing genes. In this lecture we will analyze the main technical issues associated to the possible application of NGS technique in daily practice and the possible difficulties in the interpretation of the results coming from the simultaneous analysis of different genes.
Disclosure of Interest None declared