A comprehensive genetic evaluation of five genes linked to hereditary hemorrhagic telangiectasia (HHT) was performed on a 64-year-old man with recurrent nosebleeds (two times/week). Targeted next-generation sequencing and supplemental Sanger sequencing did not identify any single nucleotide variants or small insertions/deletions. Evaluation of the data for copy number revealed a full gene deletion of ENG, encoding endoglin. Quantitative PCR of ENG confirmed a heterozygous deletion in the patient.
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This data confirms a heterozygous full gene deletion of ENG, which is pathogenic and sufficient for a diagnosis of hereditary hemorrhagic telangiectasia, type 1.
Hereditary hemorrhagic telangiectasis (HHT) is a highly penetrant, autosomal dominant disorder that is thought to be underdiagnosed. It is characterized by the abnormal development of blood vessels with recurrent nosebleeds (epistaxis) known to be a common clinical manifestation. While other clinical features supporting a diagnosis of HHT were unavailable in this case, the identification of a heterozygous, pathogenic variant in a disease-associated gene establishes the diagnosis. Based upon intrafamilial variability of clinical symptoms associated with this phenotype, evaluation of this variant in at-risk relatives would be recommended.
Approximately 44% of all pathogenic variants identified in HHT reside in ENG, encoding endoglin, and lead to the diagnosis of HHT, type 1. Endoglin is a transmembrane protein that forms homodimers expressed primarily on endothelial cells and is known to be important for the maintenance of vessel wall integrity. ENG has a haploinsufficiency score of 3, defined as providing sufficient evidence for dosage sensitivity of this gene, which confirms that a single copy of this gene is not adequate to meet the needs of the cell. Indeed, heterozygous loss-of-function variants are an established mechanism of disease for ENG. To date, a wide spectrum of pathogenic variants has been identified in ENG, ranging from single nucleotide variants to copy number variants, including full gene deletions.
Jeanne Theis, Ph.D.
Fellow, Laboratory Genetics & Genomics
Linnea Baudhuin, Ph.D.
Consultant, Laboratory Genetics & Genomics
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science