Ferran Casals

Primary immunodeficiencies (PIDs) are a group of more than 350 rare and chronic genetic disorders, in which part of the immune system functions improperly. Traditionally, PIDs included disorders originated by an increased risk to severe and recurrent infections or by opportunistic pathogens caused by genetic or developmental defects in the immune system generating biochemistry dysfunction, including transcription factors, cytokines and cytokine receptors, receptors on cell surface, intracellular signalling pathways, enzymes involved in DNA re-modeling and enzymes restricted to the immune system. Autoinflammatory diseases (AIDs) constitute a specific subgroup of primary immunodeficiency diseases that are characterized by an abnormally increased inflammation mainly mediated by cells and molecules of innate immune system. This group of diseases currently encompass more than 30 different monogenic conditions, with most of them described in the past few years as a consequence of the advances of methods of DNA sequencing.

NGS approaches, mostly WES, have allowed a molecular diagnosis of a low to moderate proportion of the PID cases, which increases with the severity and lower prevalence of the disease, and being this percentage particularly low in the case of autoinflammatory syndromes. In addition, many PIDs present clinical and phenotypical heterogeneity across the affected individuals, also hindering the medical and molecular diagnosis. In our research we explore the genetic etiology of PIDs and AIDs, both to detect new germline genetic variants as to develop new models of non-Mendelian contributions to the variability of human disease. Among others, we analyze the contribution and the effect on the clinical heterogeneity in PID of three different factors or models: (i) somatic genetic variation, (ii) modifier genes and genetic variants, and (iii) oligogenic scenarios with two or a few genes originating the disease.

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