Khoury E, et al. - In order to discover germline genetic “drivers” of Hodgkin lymphoma (HL), researchers applied Whole Exome Sequencing to rare, familial HL samples. Thereafter, they sought functional validation of prioritized candidate genes with rare, possibly pathogenic variants that co-segregate with disease within families. Between 24 and 96 such altered genes per family, 23 of which were found in more than one, were discovered when 20 affected subjects from 10 families were analyzed in a pilot study. Various proteins that regulate mitosis and mitotic checkpoints were included in these, indicating this could be a critical pathway in disease. In vitro tests were performed to determine how protein function was influenced by variants in the top two of these candidate genes, with one implicated in the first step of glycolysis and the other a cell-cycle regulated E3-ubiquitin ligase; the findings revealed a loss of function. Overall, use of pathway-analysis to recognize shared molecular disease mechanisms is proposed in this study, rather than being limited to identifying a set of genes that cause disease in a few families each.