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Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia.
- Source :
-
Blood [Blood] 2020 Oct 22; Vol. 136 (17), pp. 1907-1918. - Publication Year :
- 2020
-
Abstract
- 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.<br /> (© 2020 by The American Society of Hematology.)
- Subjects :
- Activin Receptors, Type II chemistry
Activin Receptors, Type II genetics
Cohort Studies
DNA Mutational Analysis methods
Endoglin chemistry
Endoglin genetics
Female
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
Models, Molecular
Phenotype
Retrospective Studies
Sequence Analysis, DNA methods
Smad4 Protein chemistry
Smad4 Protein genetics
Telangiectasia, Hereditary Hemorrhagic epidemiology
Telangiectasia, Hereditary Hemorrhagic pathology
Genetic Association Studies methods
Mutation
Telangiectasia, Hereditary Hemorrhagic genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 136
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 32573726
- Full Text :
- https://doi.org/10.1182/blood.2019004560