January 2023 – Laboratory Genetics and Genomics

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. 

References

1. McDonald J, Stevenson DA. Hereditary Hemorrhagic Telangiectasia. 2000 Jun 26 [updated 2021 Nov 24]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. PMID: 20301525.
   https://www.ncbi.nlm.nih.gov/books/NBK1351/
2. Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum, MJ, Ledbetter DH, Maglott DR, Martin CL, Nussbaum RL, Plon SE, Ramos EM, Sherry ST, Watson, MS, for ClinGen. ClinGen The Clinical Genome Resource. June 4, 2015. N Engl J Med 2015; 372:2235-2242. PMID: 26014595.