PhD defence F.M.P. (Fabian) Kaiser

Summary:

Inborn errors of immunity (IEI) are a heterogeneous group of diseases with a broad clinical spectrum, encompassing recurrent infections, autoimmunity, autoinflammation, allergy, and cancer. IEI are commonly caused by monogenic germline mutations resulting in loss or gain of function of the encoded protein, but can also manifest as a result of highly complex interactions of disease-causing variants with additional genetic and environmental factors. In addition, several IEI genes also cause symptoms in additional organ systems beyond the immune system, such as the nervous system. The genotypic and phenotypic spectrum of IEI thus varies broadly, sometimes even among patients with the identical underlying genetic defect. In this thesis, we unravel parts of this astonishing genotypic and phenotypic complexity by describing a new IEI, presenting novel mechanistic insights into a well-known IEI, connecting neuropsychiatric features of patients with IEIs to their underlying genetic defect, and illuminating a novel hypothesis regarding the genetic rescue of IEI by somatic mosaic variants in the mutated gene.