Whole genome sequencing based discovery of germline mutations underlying idiopathic multicentric Castleman disease

PI: Minji Byun, PhD

Institution: Washington University School of Medicine in St. Louis

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Multicentric Castleman disease (MCD) is a rare lymphoproliferative disorder, which, in severe cases, can lead to multiple organ failure and death. Human herpesvirus-8 (HHV-8) is known to cause MCD in patients with acquired immunodeficiency. On the other hand, what triggers MCD in individuals with no evidence of exposure to HHV-8 is poorly understood. The goal of this project was to investigate the role of inherited (germline) mutations in HHV-8-negative, idiopathic MCD. Two specific aims of this study were (1) whole genome sequencing based germline variant discovery, and (2) prioritization and validation of putative disease-causing variants. We assembled a cohort of patients at high genetic risk and carried out whole genome sequencing on selected individuals. Putative causative germline variants were selected through rigorous prioritization analyses, and functional studies to validate deleteriousness of these variants are currently ongoing. Our findings provide evidence that inherited variants underlie at least a subset of idiopathic MCD, and identify genetic determinants and molecular pathways in the pathogenesis of this devastating disease.