• Whole genome sequencing of 36 Hodgkin lymphoma 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.

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 one affected individual younger than 21 years of age, with the median age at diagnosis of 21.98 years of age (3 - 55 years). Family-based segregation analysis was performed for identification of coding and noncoding variants using linkage and filtering approaches. Using our tiered variant prioritization algorithm, we identified 44 HL risk variants in 28 pedigrees, of which 33 are coding, 11 are noncoding. The top 4 recurrent risk variants: a coding variant in KDR (rs56302315), a 5'UTR variant in KLHDC8B (rs387906223), a noncoding variant in an intron of PAX5 (rs147081110), and another noncoding variant in an intron of GATA3 (rs3824666). A newly identified splice variant in KDR (c.3849-2A>C) was observed for one pedigree and high confidence stopgain variants affecting IRF7 (p.W238*) and EEF2KMT (p.K116*) were also observed. Multiple truncating variants in POLR1E were found in three independent pedigrees as well. While 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.

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