Whole-exome analysis of adolescents with low VWF and heavy menstrual bleeding identifies novel genetic associations.

Adolescents with low von Willebrand factor (VWF) levels and heavy menstrual bleeding (HMB) experience significant morbidity. There is a need to better genetically characterize these patients and improve our understanding of the pathophysiology of bleeding. We performed whole-exome sequencing on 86 post-menarchal patients diagnosed with low-VWF levels (30-50 IU/dL) and HMB and compared them to 660 in-house controls. We compared the number of rare stop-gain/stop-loss and rare ClinVar pathogenic variants between cases and controls, as well as performed gene-burden and gene-set burden analyses. We found an enrichment in cases of rare stop-gain/stop-loss variants in genes involved in bleeding disorders, and an enrichment of rare ClinVar pathogenic variants in genes involved in anemias. The two most significant genes in the gene-burden analysis, CFB and DNASE2, are associated with atypical hemolytic uremia (aHUS) and severe anemia, respectively. VWF also surpassed exome-wide significance in the gene-burden analysis (p=7.31x10-6). Gene-set burden analysis revealed an enrichment of rare nonsynonymous variants in cases in several hematologically relevant pathways. Further, common variants in FERMT2, a gene involved in regulation of hemostasis and angiogenesis surpassed genome-wide significance. We demonstrate that adolescents with HMB and low-VWF have an excess of rare nonsynonymous and pathogenic variants in genes involved in disorders of bleeding and anemia. Variants of variable penetrance in these genes may contribute to the spectrum of phenotypes observed in HMB patients, and could partially explain the bleeding phenotype. By identifying the HMB patients who possess these variants, we may be able to improve risk stratification and patient outcomes.