Pathogenicity evaluation of coding germline variants identifies rare alleles enriched in hematological patients of a founder population

BackgroundThe clinical significance of most germline variants in hematological malignancies (HMs) remains unknown. This presents a challenge in the clinical setting, as the inability to accurately detect pathogenic variants can influence therapeutic decisions. Population isolates have been shown to be beneficial in pathogenic variant discovery due to presence of rare deleterious variants in relatively high frequencies. MethodsWe developed and applied PaVaDi, a computational pipeline that follows American College of Medical Genetics and Genomics (ACMG) guidelines, to evaluate the pathogenicity of germline variants in 511 HM patients from the Finnish founder population. We conducted an exome-wide burden analysis to assess the overall contribution of pathogenic variants to HMs and identified significant gene associations. We also examined genes previously associated with hematological diseases and DNA repair in more detail, and performed protein stability analyses to resolve variants of unknown significance (VUS). ResultsThe exome-wide burden analysis revealed potential pathogenic alleles in CUX2, RNPC3, and MFSD2A that have not previously been linked to HM predisposition. We also identified the largest series of CHEK2 variant carriers reported in hematological diseases, including pathogenic/likely pathogenic (P/LP) variants (n=19), Ile200Thr (i.e., Ile157Thr) (n=49), and other variants of uncertain significance (n=3). CHEK2 variants were 1.7-fold enriched in patients compared to controls (13.9% vs 8.3%, p=2x10-5). Strikingly, Ile200Thr was enriched over four-fold in acute lymphoblastic leukemia patients. Finally, protein structure stability analyses suggested novel MPO variants to be potentially highly deleterious. ConclusionsThis study highlights the importance of germline testing in hematological malignancies and demonstrates the utility of population isolates for pathogenic variant discovery. Our findings identify a significant burden of deleterious variants in HM patients, particularly in CHEK2, and underscore the potential of multi-disease joint analyses in revealing germline contributions to hematological diseases.