Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia

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 clinica...

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Published in:	Blood Vol. 136; no. 17; pp. 1907 - 1918
Main Authors:	Shovlin, Claire L., Simeoni, Ilenia, Downes, Kate, Frazer, Zoe C., Megy, Karyn, Bernabeu-Herrero, Maria E., Shurr, Abigail, Brimley, Jennifer, Patel, Dilipkumar, Kell, Loren, Stephens, Jonathan, Turbin, Isobel G., Aldred, Micheala A., Penkett, Christopher J., Ouwehand, Willem H., Jovine, Luca, Turro, Ernest
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 22-10-2020 American Society of Hematology
Subjects:	Activin Receptors, Type II - chemistry Activin Receptors, Type II - genetics Clinical Trials and Observations Cohort Studies DNA Mutational Analysis - methods Endoglin - chemistry Endoglin - genetics Female Genetic Association Studies - methods Genetic Predisposition to Disease Genetic Testing - methods Genomics - methods Growth Differentiation Factor 2 - chemistry Growth Differentiation Factor 2 - genetics Heterozygote High-Throughput Nucleotide Sequencing Humans Male Medicin och hälsovetenskap Models, Molecular Mutation Phenotype Retrospective Studies Sequence Analysis, DNA - methods Smad4 Protein - chemistry Smad4 Protein - genetics Telangiectasia, Hereditary Hemorrhagic - epidemiology Telangiectasia, Hereditary Hemorrhagic - genetics Telangiectasia, Hereditary Hemorrhagic - pathology
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Summary:	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. •HHT genotypes are clinically relevant but poorly predicted even by analysis of extensive physical and hematological phenotypic data.•High-throughput DNA sequencing, detailed phenotyping, and statistical and structural modeling contribute to a framework to better prognosticate and treat HHT. [Display omitted]
ISSN:	0006-4971 1528-0020 1528-0020
DOI:	10.1182/blood.2019004560