Hereditary Hemorrhagic Telangiectasia Type 1 (HHT1) / Osler-Weber-Rendu Disease via the ENG Gene

Hereditary hemorrhagic telangiectasia (HHT, OMIM 187300) is a disease of vascular dysplasia. HHT is characterized by the presence of arteriovenous malformations (AVMs) that involve direct connections between arteries and veins with no intervening capillary bed. AVMs can be located throughout the body and have a greater tendency towards rupture than normal blood vessels; this is often visible as telangiectases (small red or purple spots) on the lips, hands, or face of HHT patients. Recurrent nosebleeds are the most common symptom of HHT. About 20-25% of patients develop GI bleeding later in life that may lead to severe anemia (Abdalla et al. J Med Genet 40:494-502, 2003). Hepatic AVMs are found in up to 32% of patients and are often asymptomatic but can cause cirrhosis and affect cardiac output (Plauchu et al. Am J Med Genet 32:291-297, 1989; Garcia-Tsao et al. New Eng J Med 343:931-936, 2000). Cerebral AVMs (5-20% of patients) and pulmonary AVMs (30-50% of patients) are usually present at birth and may cause headaches, seizures, ischemia, hypoxemia, and hemothorax (see Shovlin and Letarte Thorax 54:714-729, 1999). The penetrance of HHT varies depending upon type (see below), and symptoms usually present by age 16 (Porteous et al. J Med Genet 29:527-530, 1992). The severity of HHT can vary widely even within families and can go unnoticed in affected individuals.

HHT is an autosomal dominant disorder caused by variants in genes encoding proteins that modulate the normally inhibitory transforming growth factor (TGF)-ß signaling pathway during cell proliferation and differentiation. The incidence of HHT is 1 in about 5,000 to 8,000 individuals. HHT affects men, women, and all ethnic groups (Govani and Shovlin Eur J Hum Genet 17:860-871, 2009). Variants in the ENG gene (OMIM 131195) account for ~50-60% of HHT cases (HHT1; OMIM 187300). ENG encodes the endothelial cell surface co-receptor endoglin that binds (TGF)-ß and is essential for vascular integrity (Ríus et al. Blood 92:4677-4690,1998). HHT1 is associated with a high incidence of pulmonary and cerebral AVMs and a higher penetrance than HHT2 in which hepatic AVMs are more common (Letteboer et al. J Med Genet 43:371-377, 2006). HHT1 is thought to have a more severe phenotype than other forms of HHT. Causative variants are found throughout the ENG gene and include primarily missense/nonsense variants. Large whole or multi-exon deletions are also common (Prigoda et al. J Med Genet 43:722-728, 2006), as are splice site variants and insertions. No predominant variant has been identified.

Variants in the ENG gene are found in ~50-60% of HHT patients.

This test provides full coverage of all coding exons of the ENG gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).