Current HHT genetic overview in Spain and its phenotypic correlation: data from RiHHTa registry

• Main Authors: Rosario Sánchez-Martínez, Adriana Iriarte, José María Mora-Luján, José Luis Patier, Daniel López-Wolf, Ana Ojeda, Miguel Angel Torralba, María Coloma Juyol, Ricardo Gil, Sol Añón, Joel Salazar-Mendiguchía, Antoni Riera-Mestre, for the RiHHTa Investigators of the Rare Diseases Working Group from the Spanish Society of Internal Medicine
• Format: Article
• Language: English
• Published: BMC 2020-06-01
• Series: Orphanet Journal of Rare Diseases
• Subjects: Hereditary hemorrhagic telangiectasia; Genetic test; Phenotype; Genotype; Rare diseases
• Online Access: http://link.springer.com/article/10.1186/s13023-020-01422-8

Abstract Background Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease with autosomal dominant inheritance. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in more than 90% of cases submitted to molecular diagnosis. Methods We used data from the RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry to describe genetic variants and to assess their genotype-phenotype correlation among HHT patients in Spain. Results By May 2019, 215 patients were included in the RiHHTa registry with a mean age of 52.5 ± 16.5 years and 136 (63.3%) were women. Definitive HHT diagnosis defined by the Curaçao criteria were met by 172 (80%) patients. Among 113 patients with genetic test, 77 (68.1%) showed a genetic variant in ACVRL1 and 36 (31.8%) in ENG gene. The identified genetic variants in ACVRL1 and ENG genes and their clinical significance are provided. ACVRL1 mutations were more frequently nonsense (50%) while ENG mutations were more frequently, frameshift (39.1%). ENG patients were significantly younger at diagnosis (36.9 vs 45.7 years) and had pulmonary arteriovenous malformations (AVMs) (71.4% vs 24.4%) and cerebral AVMs (17.6% vs 2%) more often than patients with ACVRL1 variants. Patients with ACVRL1 variants had a higher cardiac index (2.62 vs 3.46), higher levels of hepatic functional blood tests, and anemia (28.5% vs 56.7%) more often than ENG patients. Conclusions ACVRL1 variants are more frequent than ENG in Spain. ACVRL1 patients developed symptomatic liver disease and anemia more often than ENG patients. Compared to ACVRL1, those with ENG variants are younger at diagnosis and show pulmonary and cerebral AVMs more frequently.