家族性霍奇金淋巴瘤中新的易感编码和非编码变异的发现

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 <21 years, with the median age at diagnosis of 21.98 years (3-55 years). Family-based segregation analysis was performed for identification coding and noncoding variants using linkage filtering approaches. Using our tiered variant prioritization algorithm, we identified 44 HL-risk in 28 pedigrees, which 33 are 11 noncoding. The top 4 recurrent risk a KDR (rs56302315), 5' untranslated region KLHDC8B (rs387906223), an intron PAX5 (rs147081110), another GATA3 (rs3824666). A newly splice (c.3849-2A>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.