Discovery of novel predisposing coding and noncoding variants in familial Hodgkin lymphoma

•Whole genome sequencing of 36 Hodgkin lymphoma (HL) families identifies 33 coding and 11 noncoding HL-risk variants.•Recurrent damaging variants are observed in known (KDR and KLHDC8B) and novel (PAX5, GATA3, and POLR1E) predisposing loci. [Display omitted] Familial aggregation of Hodgkin lymphoma (HL) has been demonstrated in large population studies, pointing to genetic predisposition to this hematological malignancy. To understand the genetic variants associated with the development of HL, we performed whole genome sequencing on 234 individuals with and without HL from 36 pedigrees that had 2 or more first-degree relatives with HL. Our pedigree selection criteria also required at least 1 affected individual aged C) was observed for 1 pedigree, and high-confidence stop-gain variants affecting IRF7 (p.W238∗) and EEF2KMT (p.K116∗) were also observed. Multiple truncating variants in POLR1E were found in 3 independent pedigrees as well. Whereas KDR and KLHDC8B have previously been reported, PAX5, GATA3, IRF7, EEF2KMT, and POLR1E represent novel observations. Although there may be environmental factors influencing lymphomagenesis, we observed segregation of candidate germline variants likely to predispose HL in most of the pedigrees studied. Familial cases of Hodgkin lymphoma (HL) have long been recognized, but there is ongoing debate as to whether this reflects genetic predisposition or shared environmental factors. Flerlage et al report on whole genome sequencing of 234 individuals from 36 pedigrees with multiple first-degree relatives with HL identifying 44 HL risk variants in 28 pedigrees. Four variants were recurrent, but the others were private, occurring in only 1 family. This suggests that germline variants play a major role in familial recurrence of HL.