Monogenic immune disorders in adults: from Mendelian inheritance to somatic mosaicism

Disease manifestations of monogenic immune disorders, such as immunodeficiency, autoinflammation or autoimmunity, can be delayed until adulthood and this is mediated through various genetic mechanisms, extending beyond Mendelian inheritance. Despite the discovery of multiple genetic causes in the last decade, most patients lack a molecular diagnosis preventing personalized care. Furthermore, while the role of pathogenic somatic variants is becoming more widely recognized, the underlying molecular mechanisms remain unknown. Using state-of-the art sequencing technology and in vitro functional validation tools, I aim to define new monogenic inborn errors of immunity and unravel disease mechanisms in selected adult patients presenting with symptoms suggestive of immune dysregulation. Thorough functional validation of candidate variants is pivotal for individual patient care (diagnosis, rational design/choice of therapy, prognosis, and familial genetic counseling) and holds the promise to provide essential insights in human immunology through analysis of experiments by nature, as this research track has demonstrated in the recent past. By deciphering the molecular determinants of carefully selected adult-onset immune disorders, this project will advance the area of immunogenetics research, explore uncharted territory, and pave the way for precision treatment.