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

• Authors: Robert Sidonio Jr, Emory University; Brooke Sadler, Washington Univ; Charles G Minard, Baylor College of Medicine; Gabe Haller, Washington University in St. Louis; Christina A Gurnett, Washington University in St. Louis; Sarah H O'Brien, Nationwide Children’s Hospital; Allison Wheeler, Vanderbilt University; Shilpa Jain, Oishei Children’s Hospital; Mutka Sharma, University of Missouri Kansas City; Ayesha Zia, University of Texas Southwestern Medical Center; Roshni Kulkarni, Michigan State University; Eric Mullins, Cincinnati Children’s Hospital Medical Center; Margaret Ragni, University of Pittsburgh; Robert Sidonio, Emory University; Jennifer E Dietrich, Baylor College of Medicine; Peter A Kouides, University of Rochester; Jorge Di Paola, Washington University in St. Louis; Lakshmi Srivaths, Baylor College of Medicine
• Journal Title: BLOOD ADVANCES
• Volume: Volume 6, Number 2
• Publisher: ELSEVIER | 2022-01-25, Pages 420-428
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1182/bloodadvances.2021005118
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Hematology; VON-WILLEBRAND-FACTOR; HEMOLYTIC-UREMIC SYNDROME; IRON-DEFICIENCY ANEMIA; RARE VARIANTS; YOUNG-WOMEN; LOCI; MENORRHAGIA; DISORDERS; DISEASE; ERYTHROPOIESIS

Abstract

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.