Whole genome sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variants

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Title: Whole genome sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variants
Authors: Joyce, KE
Onabanjo, E
Brownlow, S
Nur, F
Olupona, K
Fakayode, K
Sroya, M
Thomas, GA
Ferguson, T
Redhead, J
Millar, CM
Cooper, N
Layton, DM
Boardman-Pretty, F
Caulfield, MJ
Genomics England Research Consortium, GE
Shovlin, CL
Item Type: Journal Article
Abstract: The abnormal vascular structures of hereditary hemorrhagic telangiectasia (HHT) often cause severe anemia due to recurrent hemorrhage, but HHT-causal genes do not predict the severity of hematological complications. We tested for chance inheritance and clinical associations of rare deleterious variants where loss-of-function causes bleeding or hemolytic disorders in the general population. In double-blinded analyses, all 104 HHT patients from a single reference centre recruited to the 100,000 Genomes Project were categorised on new MALO (more/as-expected/less/opposite) sub-phenotype severity scales, and whole genome sequencing data tested for high impact variants in 75 HHT-independent genes encoding coagulation factors, platelet, hemoglobin, erythrocyte enzyme and erythrocyte membrane constituents. Rare variants (all GnomAD allele frequencies <0.003) were identified in 56 (75%) of these 75 HHT-unrelated genes, and in 38/104 (36.5%) of the HHT patients. Likely deleteriousness assignments by Combined Annotation Dependent Depletion (CADD) scores >15 were supported by gene-level mutation significance cutoff (MSC) scores. CADD>15 variants were found for 1 in 10 patients within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to HHT vessels had more CADD-deleterious variants in platelet (Spearman ρ=0.25, p=0.008) and coagulation (Spearman ρ=0.21, p=0.024) genes. However, the HHT cohort had 60% fewer deleterious variants in platelet and coagulation genes than expected (Mann Whitney p=0.021). In conclusion, HHT patients commonly have rare variants in genes of relevance to their phenotype, offering new therapeutic targets and opportunities for informed, personalised medicine strategies.
Issue Date: 7-Jul-2022
Date of Acceptance: 21-Feb-2022
URI: http://hdl.handle.net/10044/1/98445
DOI: 10.1182/bloodadvances.2022007136
ISSN: 2473-9529
Publisher: American Society of Hematology
Start Page: 3956
End Page: 3969
Journal / Book Title: Blood Advances
Volume: 6
Issue: 13
Copyright Statement: © 2022 by The American Society of Hematology. Licensed under Creative CommonsvAttribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permit- ting only noncommercial, nonderivative use with attribution. All other rights reserved.
Sponsor/Funder: Imperial College Healthcare NHS Trust
Funder's Grant Number: RDC01
Keywords: Activin Receptors, Type II
Telangiectasia, Hereditary Hemorrhagic
Genomics England Research Consortium
Telangiectasia, Hereditary Hemorrhagic
Activin Receptors, Type II
Genetic Variation
Whole Genome Sequencing
Publication Status: Published
Conference Place: United States
Open Access location: https://ashpublications.org/bloodadvances/article/doi/10.1182/bloodadvances.2022007136/484454/Whole-genome-sequences-discriminate-hereditary
Online Publication Date: 2022-03-22
Appears in Collections:Department of Immunology and Inflammation
Department of Surgery and Cancer
National Heart and Lung Institute

This item is licensed under a Creative Commons License Creative Commons