Imperial College London
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DrCarolynMillar

Faculty of Medicine, Department of Immunology and Inflammation

Honorary Clinical Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 3313 2153c.millar

 
 
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Location

 

Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Joyce:2022:10.1182/bloodadvances.2022007136,
author = {Joyce, KE and Onabanjo, E and Brownlow, S and Nur, F and Olupona, K and Fakayode, K and Sroya, M and Thomas, GA and Ferguson, T and Redhead, J and Millar, CM and Cooper, N and Layton, DM and Boardman-Pretty, F and Caulfield, MJ and Genomics, England Research Consortium GE and Shovlin, CL},
doi = {10.1182/bloodadvances.2022007136},
journal = {Blood Advances},
pages = {3956--3969},
title = {Whole genome sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variants},
url = {http://dx.doi.org/10.1182/bloodadvances.2022007136},
volume = {6},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Joyce,KE
AU  - Onabanjo,E
AU  - Brownlow,S
AU  - Nur,F
AU  - Olupona,K
AU  - Fakayode,K
AU  - Sroya,M
AU  - Thomas,GA
AU  - Ferguson,T
AU  - Redhead,J
AU  - Millar,CM
AU  - Cooper,N
AU  - Layton,DM
AU  - Boardman-Pretty,F
AU  - Caulfield,MJ
AU  - Genomics,England Research Consortium GE
AU  - Shovlin,CL
DO  - 10.1182/bloodadvances.2022007136
EP  - 3969
PY  - 2022///
SN  - 2473-9529
SP  - 3956
TI  - Whole genome sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variants
T2  - Blood Advances
UR  - http://dx.doi.org/10.1182/bloodadvances.2022007136
UR  - https://www.ncbi.nlm.nih.gov/pubmed/35316832
UR  - http://hdl.handle.net/10044/1/98445
VL  - 6
ER  -
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