Imperial College London
Alternate

Claire L. Shovlin PhD FRCP

Faculty of Medicine, National Heart & Lung Institute

Professor of Practice (Clinical and Molecular Medicine)
 
 
 
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Contact

 

c.shovlin Website

 
 
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Location

 

534Block L Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Shovlin:2020:10.1182/blood.2019004560,
author = {Shovlin, C and Simeoni, I and Downes, K and Frazer, Z and Megy, K and Bernabeu-Herrero, M and Shurr, A and Brimley, J and Patel, D and Kell, L and Stephens, J and Turbin, I and Aldred, M and Penkett, C and Stirrups, K and Ouwehand, W and Jovine, L and Turro, E},
doi = {10.1182/blood.2019004560},
journal = {Blood},
pages = {1907--1918},
title = {Mutational and phenotypic characterisation of hereditary hemorrhagic telangiectasia},
url = {http://dx.doi.org/10.1182/blood.2019004560},
volume = {136},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Care delivery for HHT patients is impeded by the need for laborious, repeated phenotyping and gaps in knowledge regarding the relationships between causal DNA variants in ENG, ACVRL1, SMAD4 and GDF2, and clinical manifestations. To address this, we analyzed DNA samples from 183 previously uncharacterized, unrelated HHT and suspected HHT cases using the ThromboGenomics high-throughput sequencing platform. We identified 127 rare variants across 168 heterozygous genotypes. Applying modified American College of Medical Genetics and Genomics Guidelines, 106 variants were classified as pathogenic/likely pathogenic and 21 as nonpathogenic (variant of uncertain significance/benign). Unlike the protein products of ACVRL1 and SMAD4, the extracellular ENG amino acids are not strongly conserved. Our inferences of the functional consequences of causal variants in ENG were therefore informed by the crystal structure of endoglin. We then compared the accuracy of predictions of the causal gene blinded to the genetic data using 2 approaches: subjective clinical predictions and statistical predictions based on 8 Human Phenotype Ontology terms. Both approaches had some predictive power, but they were insufficiently accurate to be used clinically, without genetic testing. The distributions of red cell indices differed by causal gene but not sufficiently for clinical use in isolation from genetic data. We conclude that parallel sequencing of the 4 known HHT genes, multidisciplinary team review of variant calls in the context of detailed clinical information, and statistical and structural modeling improve the prognostication and treatment of HHT.
AU  - Shovlin,C
AU  - Simeoni,I
AU  - Downes,K
AU  - Frazer,Z
AU  - Megy,K
AU  - Bernabeu-Herrero,M
AU  - Shurr,A
AU  - Brimley,J
AU  - Patel,D
AU  - Kell,L
AU  - Stephens,J
AU  - Turbin,I
AU  - Aldred,M
AU  - Penkett,C
AU  - Stirrups,K
AU  - Ouwehand,W
AU  - Jovine,L
AU  - Turro,E
DO  - 10.1182/blood.2019004560
EP  - 1918
PY  - 2020///
SN  - 0006-4971
SP  - 1907
TI  - Mutational and phenotypic characterisation of hereditary hemorrhagic telangiectasia
T2  - Blood
UR  - http://dx.doi.org/10.1182/blood.2019004560
UR  - https://ashpublications.org/blood/article/136/17/1907/461102/Mutational-and-phenotypic-characterization-of
UR  - http://hdl.handle.net/10044/1/79705
VL  - 136
ER  -
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