Genetic Variants and Clinical Phenotypes in Korean Patients With Hereditary Hemorrhagic Telangiectasia
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Objectives. Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by recurrent epistaxis, telangiectasia, and visceral arteriovenous malformations (AVMs). Activin A receptor-like type 1 (ACVRL1/ALK1) and endoglin (ENG) are the principal genes whose mutations cause HHT. No multicenter study has yet investigated correlations between genetic variations and clinical outcomes in Korean HHT patients. Methods. Seventy-two members from 40 families suspected to have HHT based on symptoms were genetically screened for pathogenic variants of ACVRL1 and ENG. Patients with genetically diagnosed HHT were also evaluated. Results. In the HHT genetic screening, 42 patients from 24 of the 40 families had genetic variants that met the pathogenic criteria (pathogenic very strong, pathogenic strong, pathogenic moderate, or pathogenic supporting) based on the American College of Medical Genetics and Genomics Standards and Guidelines for either ENG or ACVRL1: 26 from 12 families (50%) for ENG, and 16 from 12 families (50%) for ACVRL1. Diagnostic screening of 42 genetically positive HHT patients based on the Curaçao criteria revealed that 24 patients (57%) were classified as having definite HHT, 17 (41%) as having probable HHT, and 1 (2%) as unlikely to have HHT. Epistaxis was the most common clinical presentation (38/42, 90%), followed by visceral AVMs (24/42, 57%) and telangiectasia (21/42, 50%). Five patients (12%) did not have a family history of HHT clinical symptoms. Conclusion. Only approximately half of patients with ACVRL1 or ENG genetic variants could be clinically diagnosed as having definite HHT, suggesting that genetic screening is important to confirm the diagnosis.
Abstract
Objectives. Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by recurrent epistaxis, telangiectasia, and visceral arteriovenous malformations (AVMs). Activin A receptor-like type 1 (ACVRL1/ALK1) and endoglin (ENG) are the principal genes whose mutations cause HHT. No multicenter study has yet investigated correlations between genetic variations and clinical outcomes in Korean HHT patients. Methods. Seventy-two members from 40 families suspected to have HHT based on symptoms were genetically screened for pathogenic variants of ACVRL1 and ENG. Patients with genetically diagnosed HHT were also evaluated. Results. In the HHT genetic screening, 42 patients from 24 of the 40 families had genetic variants that met the pathogenic criteria (pathogenic very strong, pathogenic strong, pathogenic moderate, or pathogenic supporting) based on the American College of Medical Genetics and Genomics Standards and Guidelines for either ENG or ACVRL1: 26 from 12 families (50%) for ENG, and 16 from 12 families (50%) for ACVRL1. Diagnostic screening of 42 genetically positive HHT patients based on the Curaçao criteria revealed that 24 patients (57%) were classified as having definite HHT, 17 (41%) as having probable HHT, and 1 (2%) as unlikely to have HHT. Epistaxis was the most common clinical presentation (38/42, 90%), followed by visceral AVMs (24/42, 57%) and telangiectasia (21/42, 50%). Five patients (12%) did not have a family history of HHT clinical symptoms. Conclusion. Only approximately half of patients with ACVRL1 or ENG genetic variants could be clinically diagnosed as having definite HHT, suggesting that genetic screening is important to confirm the diagnosis.
참고문헌 (25)
- Shovlin CL, "Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment", Blood Rev, 24(6), pp.203~219 (2010)
- Shovlin CL, "Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)", Am J Med Genet, 91(1), pp.66~67 (2000)
- AAssar OS, "The natural history of epistaxis in hereditary hemorrhagic telangiectasia", Laryngoscope, 101(9), pp.977~980 (1991)
- Kjeldsen AD, "Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia", Am J Gastroenterol, 95(2), pp.415~418 (2000)
- Kjeldsen AD, "Prevalence of pulmonary arteriovenous malformations (PAVMs) and occurrence of neurological symptoms in patients with hereditary haemorrhagic telangiectasia (HHT)", J Intern Med, 248(3), pp.255~262 (2000)
- Larsen L, "Prevalence of hereditary hemorrhagic telangiectasia in patients operated for cerebral abscess: a retrospective cohort analysis", Eur J Clin Microbiol Infect Dis, 36(10), pp.1975~1980 (2017)
- McAllister KA, "Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1", Nat Genet, 8(4), pp.345~351 (1994)
- Abdalla SA, "Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease", J Med Genet, 43(2), pp.97~110 (2006)
- McDonald J, "Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era", Front Genet, 6, pp.1~ (2015)
- University of Utah, "ARUP scientific resource for research and education: HHT disease databases" (2011), ARUP Laboratories
- 이승태, "Clinical Features and Mutations in the ENG, ACVRL1, and SMAD4 genes in Korean Patients with Hereditary Hemorrhagic Telangiectasia", Journal of Korean Medical Science, 24(1), pp.69~76 (2009), 대한의학회
- Kim MJ, "Clinical and genetic analyses of three Korean families with hereditary hemorrhagic telangiectasia", BMC Med Genet, 12, pp.130~ (2011)
- Ha M, "Gastric angiodysplasia in a hereditary hemorrhagic telangiectasia type 2 patient", World J Gastroenterol, 18(15), pp.1840~1844 (2012)
- Adzhubei IA, "A method and server for predicting damaging missense mutations", Nat Methods, 7(4), pp.248~249 (2010)
- Sim NL, "SIFT web server: predicting effects of amino acid substitutions on proteins", Nucleic Acids Res, 40, pp.W452~W457 (2012)
- Choi Y, "PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels", Bioinformatics, 31(16), pp.2745~2747 (2015)
- Richards S, "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology", Genet Med, 17(5), pp.405~424 (2015)
- Torring PM, "National mutation study among Danish patients with hereditary haemorrhagic telangiectasia", Clin Genet, 86(2), pp.123~133 (2014)
- Chen YJ, "Clinical and genetic characteristics of Chinese patients with hereditary haemorrhagic telangiectasia-associated pulmonary hypertension", Eur J Clin Invest, 43(10), pp.1016~1024 (2013)
- Alaa El Din F, "Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by hereditary hemorrhagic telangiectasia", PLoS One, 10(7), pp.e0132111~ (2015)
- Komiyama M, "Hereditary hemorrhagic telangiectasia in Japanese patients", J Hum Genet, 59(1), pp.37~41 (2014)
- Martin Koenighofer, "Spectrum of Novel Hereditary Hemorrhagic Telangiectasia Variants in an Austrian Patient Cohort", Clinical and Experimental Otorhinolaryngology, 12(4), pp.405~411 (2019), 대한이비인후과학회[DOI]
- Karlsson T, "Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia: experience from the Center for Osler’s Disease, Uppsala University Hospital", Ups J Med Sci, 123(3), pp.153~157 (2018)
- van Gent MW, "Hereditary hemorrhagic telangiectasia: how accurate are the clinical criteria?", Am J Med Genet A, 161(3), pp.461~466 (2013)
- Wooderchak-Donahue WL, "Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in hereditary haemorrhagic telangiectasia", J Med Genet, 55(12), pp.824~830 (2018)