OC 78.4 - Haemorrhagic sub-phenotypes in hereditary haemorrhagic telangiectasia are associated with high impact DNA variants in platelet/coagulation genes responsible for general population bleeding disorders

Wednesday, July 13, 2022

11:00 AM – 11:15 AM

Location: ExCel Center, ICC Capital Suite Room 1

Presentation Format: Virtual

Co-Author(s)

KJ

Katie Joyce

Medical student
Imperial College School of Medicine
London, England, United Kingdom
EO

Ebun Onabanjo

Clinical Coordinator
Imperial College Healthcare NHS Trust
London, England, United Kingdom
SB

Sheila Brownlow

Clinical Coordinator
Imperial College Healthcare NHS Trust
London, England, United Kingdom
FN

Fadumo Nur

Genomic Coordinator
Imperial College Healthcare NHS Trust
London, England, United Kingdom
KO

Kike Olupona

Genomic Coordinator
Imperial College Healthcare NHS Trust
London, England, United Kingdom
KF

Kehinde Fakayode

Genomic Coordinator
Imperial College Healthcare NHS Trust
London, England, United Kingdom
MS

Manveer Sroya

Pathology Coordinator
Imperial College London
London, England, United Kingdom
GT

Geraldine Thomas

Professor of Molecular Pathology
Imperial College London
London, England, United Kingdom
TF

Teena Ferguson

West London Genomic Medicine Centre
Imperial College Healthcare NHS Trust
London, England, United Kingdom
JR

Julian Redhead

Professor of Practice and Medical Director, West London Genomic Medicine Centre
Imperial College Healthcare NHS Trust
London, England, United Kingdom
Carolyn Millar, MD

Consultant Haematologist
Imperial College Healthcare NHS Trust
London, England, United Kingdom
Nichola Cooper, MS (Cantab), MBBS, MD, FRCP, FRCPath,

Department of Medicine
Hammersmith Hospital
London, England, United Kingdom
ML

Mark Layton

Professor of Practice (Haematology)
Imperial College London
London, England, United Kingdom
FB

Freya Boardman-Pretty

GeCIP Rare Disease Manager
Genomics England
London, England, United Kingdom
MC

Mark Caulfield

Chief Scientist
Genomics England
London, England, United Kingdom
GR

Genomics England Research Consortium

Research Consortium
Genomics England
London, England, United Kingdom

Presenting Author(s)

Claire L. Shovlin, MA (Cantab) PhD FRCP FAoP

Professor of Practice (Clinical and Molecular Medicine)
Imperial College London
London, England, United Kingdom

Background: Hereditary haemorrhagic telangiectasia (HHT) is an endothelial vasculopathy inherited as an autosomal dominant trait, due to a heterozygous loss-of-function variant in ACVRL1, ENG or SMAD4. Abnormal HHT vascular structures often cause anaemia due to recurrent haemorrhage, with published evidence for anaemia out-of-proportion to haemorrhage in one-third of severely anaemic patients. HHT-causal genes do not predict the severity of haematological complications.

Aims: Our aims were to test whether rare, high-impact variation in genes beyond the primary HHT-causative gene could play a role in the variable degrees of haemorrhage and anaemia exhibited by HHT patients.

Methods: We tested for chance inheritance and clinical associations of rare deleterious variants where loss-of-function causes bleeding or haemolytic 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 assigned to sub-phenotype severity scales, and whole genome sequencing data tested for high impact variants in 75 HHT-independent genes encoding coagulation factors, platelet, haemoglobin, erythrocyte enzyme and erythrocyte membrane constituents.

Results: Rare variants (all GnomAD allele frequencies < 0.003) were identified in 38/104 (36.5%) of the HHT patients, and in 56 (75%) of the 75 HHT-unrelated genes. 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 haemolytic genes. In blinded analyses, patients with greater haemorrhagic 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).

Conclusion(s): HHT patients with deleterious variants in genes relevant to haemorrhage/anaemia display more haemorrhagic phenotypes.