This project focuses on functional and epidemiological studies to elucidate the clinical significance of genetic variants in cytotoxicity-related genes. Familial hemophagocytic lymphohistiocytosis (HLH) type 2 is a genetic disorder of lymphocyte cytotoxicity, caused by homozygous mutations in the PRF1 gene. Biallelic null mutations in PRF1 lead to absent cytotoxicity and predispose affected individuals to the life-threatening hyperinflammatory syndrome of HLH. Hypomorphic PRF1 variants allow residual cytotoxicity and can cause later onset of HLH. Patients with null mutations require hematopoietic stem-cell transplantation (HSCT) as curative therapy. In patients with hypomorphic mutations, this therapeutic decision is less clear. More data is needed to support clinical decisions in mutation carriers, in particular since FHL2 is an attractive target for newborn screening.
The PRF1 A91V polymorphism is a hypomorphic allele as it affects PRF1 stability and reduces its expression by 50%. However, population-based studies have shown that homozygous A91V does not affect health or longevity. Uncertainty remains, whether this is also true if A91V pairs in trans with a severe PRF1 mutation (“X”). Compound heterozygous patients with A91V/X and HLH have been described, but the contribution of the genetic defect to HLH is disputed. The risk of HLH recurrence is therefore unclear, rendering the decision difficult whether or not to perform HSCT.
We examine the functional consequences of different compound heterozygous constellations of PRF1 variants on lymphocyte cytotoxicity. In parallel, we study the prevalence of these compound heterozygous individuals on a population level, exploring large biobank datasets to study genotype-phenotype correlations. We additionally use novel AI-driven approaches for evaluating pathogenicity of cytotoxicity-related genes.
