Variant distribution and characterization of hereditary hemorrhagic telangiectasia in Chinese patients

Abstract

Background: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder with variable manifestations, including recurrent epistaxis, telangiectasias, arteriovenous malformations, and family history. It is caused by heterozygous null alleles of ENG, ACVRL1, SMAD4, or BMP9, with delayed clinical diagnosis. Genetic testing is crucial for early diagnosis.

Objective: To analyze the variant distribution of HHT-related genes, expand variant databases for Chinese patients, and explore phenotype-genotype associations.

Methods: Thirty-two individuals from 20 unrelated families were recruited. Coding regions of ENG, ACVRL1, SMAD4, and BMP9 were sequenced. Variants were identified by sequence alignment. Epistaxis severity was evaluated using the epistaxis severity score (ESS), and the ESS differences between groups were analyzed using the Mann–Whitney test.

Results: Seventeen unique variants were identified in 17 unrelated HHT families (17/20, 85%), including 5 novel variants (3 in ENG and 2 in ACVRL1). Eleven ACVRL1 variants were identified in 12 families (12/17, 70.6%). Six variants of ENG were detected in 5 families (5/17, 29.4%), and one patient had two variants. ACVRL1 variants were 2.4 times more prevalent than ENG variants, with 41.7% of ACVRL1 variants in exon 10. A recurrent variant, c.1435C>T, was identified in two families. Epistaxis severity increased with age.

Conclusions: ACVRL1 variants were more common than ENG variants in Chinese HHT families, with exon 10 identified as a potential hotspot. These findings enhance understanding of HHT genetics and guide targeted genetic testing in China.

Keywords

ACVRL1 / ENG / epistaxis / Hereditary hemorrhagic telangiectasia / variants

References

[1] Dakeishi M , Shioya T , Wada Y , et al. Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan. Hum Mutat. 2002; 19 (2): 140- 148.

[2] Shovlin CL , Guttmacher AE , Buscarini E , et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000; 91 (1): 66- 67.

[3] McDonald J , Wooderchak-Donahue W , VanSant Webb C , Whitehead K , Stevenson DA , Bayrak-Toydemir P . Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet. 2015; 6: 1.

[4] Porteous ME , Burn J , Proctor SJ . Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet. 1992; 29 (8): 527- 530.

[5] Pierucci P , Lenato GM , Suppressa P , et al. A long diagnostic delay in patients with Hereditary Haemorrhagic Telangiectasia: a questionnaire-based retrospective study. Orphanet J Rare Dis. 2012; 7 (1): 33.

[6] Shovlin CL , Simeoni I , Downes K , et al. Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia. Blood. 2020; 136 (17): 1907- 1918.

[7] McAllister KA , Grogg K , Johnson D , et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994; 8 (4): 345- 351.

[8] Johnson DW , Berg J , Baldwin M , et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996; 13 (2): 189- 195.

[9] Gallione CJ , Richards JA , Letteboer TGW , et al. SMAD4 mutations found in unselected HHT patients. J Med Genet. 2006; 43 (10): 793- 797.

[10] Wooderchak-Donahue WL , McDonald J , O’Fallon B , et al. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet. 2013; 93 (3): 530- 537.

[11] McDonald J , Damjanovich K , Millson A , et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011; 79 (4): 335- 344.

[12] Zhao Y , Zhang Y , Wang X , Zhang L . Variant analysis in Chinese families with hereditary hemorrhagic telangiectasia. Mol Genet Genomic Med. 2019; 7 (9): e893.

[13] Hoag JB , Terry P , Mitchell S , Reh D , Merlo CA . An epistaxis severity score for hereditary hemorrhagic telangiectasia. Laryngoscope. 2010; 120 (4): 838- 843.

[14] Ng PC , Henikoff S . Predicting deleterious amino acid substitutions. Genome Res. 2001; 11 (5): 863- 874.

[15] Larkin MA , Blackshields G , Brown N , et al. Clustal W and clustal X version 2.0. Bioinformatics. 2007; 23 (21): 2947- 2948.

[16] Richards S , Aziz N , Bale S , et al. 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. 2015; 17 (5): 405- 424.

[17] Kitayama K , Ishiguro T , Komiyama M , et al. Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia. BMC Med Genom. 2021; 14 (1): 288.

[18] Kim BG , Jung J , Kim MJ , et al. Genetic variants and clinical phenotypes in Korean patients with hereditary hemorrhagic telangiectasia. Clin Exp Otorhinolaryngol. 2021; 14 (4): 399- 406.

[19] Abdalla SA , Cymerman U , Rushlow D , et al. Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia. Hum Mutat. 2005; 25 (3): 320- 321.

[20] Bayrak-Toydemir P , McDonald J , Markewitz B , et al. Genotypephenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Am J Med Genet A. 2006; 140 (5): 463- 470.

[21] Brusgaard K , Kjeldsen A , Poulsen L , et al. Mutations in endoglin and in activin receptor-like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2004; 66 (6): 556- 561.

[22] Lesca G , Olivieri C , Burnichon N , et al. Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network. Genet Med. 2007; 9 (1): 14- 22.

[23] Faughnan ME , Mager JJ , Hetts SW , et al. Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann Intern Med. 2020; 173 (12): 989- 1001.

[24] Bernabeu-Herrero ME , Patel D , Bielowka A , et al. Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT. Blood. 2024; 143 (22): 2314- 2331.

[25] Joyce KE , Onabanjo E , Brownlow S , et al. Whole genome sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variation. Blood Adv. 2022; 6 (13): 3956- 3969.

RIGHTS & PERMISSIONS

The Author(s). Eye & ENT Research published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.