PORTFOLIO

Primary immunodeficiency diseases (PID) are a heterogeneous group of rare disorders that affect the immune system and cause an increased number of serious infections in affected individuals. Most patients affected with PID are identified in childhood, but an increasing number of conditions interfering with the normal function of the immune system are also discovered in adult individuals. About 300 forms of PID are currently known and while several conditions have easily recognizable clinical presentations, in many cases different diseases have overlapping and common clinical features. In addition, atypical presentations of well-known syndromes often complicate the clinical interpretation. Genetic analysis offers the possibility of establishing a definitive diagnosis, which is of paramount importance to make prognostic assessments and to provide patients and families adequate clinical management and genetic counseling. The objective of this project is, therefore, to establish a diagnostic platform that will allow to determine the genetic component that underlies the disease phenotype. A complementary objective of the project is to characterize the mechanisms of the immune systems that are affected by the genetic mutations, which will provide additional notions of how the immune system develops and works in health and disease.

This project has taken advantage of the recent revolution of genomic analysis brought about by the development of high-throughput, next generation sequencing (NGS) methods to perform screening of genes responsible for known forms of PIDs, as well as of candidate genomic regions that may be implicated in the pathophysiology of still undefined immunologic defects. Using cutting edge methods of molecular and cellular biology (e.g. CRISPR/Cas-9, iPS cells), this project is developing cellular models that recapitulate the immune defects observed in humans, which will inform the developments of new forms of therapies for PIDs.

We have identified 362 genes that are either known to be at the basis of or can be hypothesized to be associated with various forms of PIDs. A library of primers covering the coding sequences of such genes has been generated that results in around 5500 amplified sequences. After validation of the NGS platform using DNA samples from healthy control subjects and patients affected with known forms of PID, a series of 60 samples from pediatric and adult patients with clinical diagnosis of PID were then sequenced and analyzed. Such process resulted in the definition of 12 molecular diagnoses (20% of cases), as well as the identification of a potential new mechanism of a new autoinflammatory disease that is currently being modeled in the laboratory.

Droz-Georget S, Riccio O, Royer-Bertrand B, Superti-Furga A, Candotti F. [Next generation sequencing: a diagnostic tool for inherited immune defects]. Rev Med Suisse. 2017 Apr 5;13(557):763-766. French. PubMed PMID: 28722367.