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Author Notes:

Jorge Di Paola, 660 South Euclid Ave, Campus Box 8208, Washington University in St. Louis, St. Louis, MO 63110; e-mail: dipaolaj@wustl.edu

akshmi Srivaths, Gulf States Hemophilia and Thrombophilia Center, University of Texas Health Science Center at Houston and McGovern School of Medicine, 6655 Travis St, Suite 400 HMC, Houston, TX 77030; e-mail: lakshmi.v.srivaths@uth.tmc.edu

B.S., L.S., J.E.D., and P.A.K. conceived the study; B.S. and G.H. performed all genetic analyses; C.G.M. analyzed the clinical phenotype data; G.H. and C.A.G. provided control samples; L.S., P.A.K., S.H.O., A.W., S.J., M.S., A.Z., R.K., M.V.R., R.S., and J.E.D. collected samples; and B.S. and J.E.D. wrote the manuscript; and all authors reviewed the manuscript.

The authors declare no competing financial interests.


Research Funding:

This work was supported by an investigator-initiated research grant (IIR[1]USA-BXLT-001980-H16-30985) from Shire US Inc., now part of Takeda (L.S.).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Hematology
  • LOCI

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

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Journal Title:



Volume 6, Number 2


, Pages 420-428

Type of Work:

Article | Final Publisher PDF


Adolescents with low von Willebrand factor (VWF) levels and heavy menstrual bleeding (HMB) experience significant morbidity. There is a need to better characterize these patients genetically and improve our understanding of the pathophysiology of bleeding. We performed whole-exome sequencing on 86 postmenarchal patients diagnosed with low VWF levels (30-50 IU/dL) and HMB and compared them with 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 2 most significant genes in the gene burden analysis, CFB and DNASE2, are associated with atypical hemolytic uremia and severe anemia, respectively. VWF also surpassed exome-wide significance in the gene burden analysis (P = 7.31 x 1026). 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 the 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 bleeding disorders and anemia. Variants of variable penetrance in these genes may contribute to the spectrum of phenotypes observed in patients with HMB and could partially explain the bleeding phenotype. By identifying patients with HMB who possess these variants, we may be able to improve risk stratification and patient outcomes.

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© 2022 by The American Society of Hematology.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/rdf).
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