Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2)

Genetics in Medicine volume 22, pages1201–1205(2020)Cite this article

Abstract

Purpose

Determine the variant detection rate for ENG, ACVRL1, and SMAD4 in individuals who meet consensus (Curaçao) criteria for the clinical diagnosis of hereditary hemorrhagic telangiectasia.

Methods

Review of HHT center database for individuals with three or more HHT diagnostic criteria, in whom molecular genetic analysis for ENG, ACVRL1, and SMAD4 had been performed.

Results

A variant known or suspected to be causal was detected in ENG in 67/152 (44.1%; 95% confidence interval [CI], 36.0–52.4%), ACVRL1 in 79/152 (52.0%; 95% CI, 43.7–60.1%), and SMAD4 in 2/152 (1.3%; 95% CI, 0.2–4.7%) family probands with definite HHT. Only 4/152 (2.6%; 95% CI, 0.7–6.6%) family probands did not have a variant in one of these genes.

Conclusion

Previous reports of the variant detection rate for ENG and ACVRL1 in HHT patients have come from laboratories, which receive samples from clinicians with a wide range of expertise in recognizing clinical manifestations of HHT. These studies suggest a significantly lower detection rate (~75–85%) than we have found in patients who meet strictly applied consensus criteria (96.1%). Analysis of SMAD4 adds an additional detection rate of 1.3%. HHT as defined by the Curaçao criteria is highly predictive of a causative variant in either ENG or ACVRL1.

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References

  1. 1.

    Marchuk DA, Guttmacher AE, Penner JA, Ganguly P. Report on the workshop on hereditary hemorrhagic telangiectasia, July 10-11, 1997. Am J Med Genet. 1998;76:269–273.

    CAS  Article  Google Scholar 

  2. 2.

    Berg J, Porteous M, Reinhardt D, et al. Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations. J Med Genet. 2003;40:585–590.

    CAS  Article  Google Scholar 

  3. 3.

    Plauchu H, de Chadarevian JP, Bideau A, Robert JM. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet. 1989;32:291–297.

    CAS  Article  Google Scholar 

  4. 4.

    Porteous ME, Burn J, Proctor SJ. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet. 1992;29:527–530.

    CAS  Article  Google Scholar 

  5. 5.

    Morgan T, McDonald J, Anderson C, et al. Intracranial hemorrhage in infants and children with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome). Pediatrics. 2002;109:E12.

    Article  Google Scholar 

  6. 6.

    Faughnan ME, Palda VA, Garcia-Tsao G, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011;48:73–87.

    CAS  Article  Google Scholar 

  7. 7.

    Shovlin CL, Hughes JM, Tuddenham EG, et al. A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3. Nat Genet. 1994;6:205–209.

    CAS  Article  Google Scholar 

  8. 8.

    Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996;13:189–195.

    CAS  Article  Google Scholar 

  9. 9.

    Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363:852–859.

    CAS  Article  Google Scholar 

  10. 10.

    Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet. 2006;43:97–110.

    CAS  Article  Google Scholar 

  11. 11.

    Cole SG, Begbie ME, Wallace GM, Shovlin CL. A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5. J Med Genet. 2005;42:577–582.

    CAS  Article  Google Scholar 

  12. 12.

    Bayrak-Toydemir P, McDonald J, Akarsu N, et al. A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet A. 2006;140:2155–2162.

    Article  Google Scholar 

  13. 13.

    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;93:530–537.

    CAS  Article  Google Scholar 

  14. 14.

    Bayrak-Toydemir P, Mao R, Lewin S, McDonald J. Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians. Genet Med. 2004;6:175–191.

    CAS  Article  Google Scholar 

  15. 15.

    Bossler AD, Richards J, George C, Godmilow L, Ganguly A. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat. 2006;27:667–675.

    CAS  Article  Google Scholar 

  16. 16.

    Prigoda NL, Savas S, Abdalla SA, et al. Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations. J Med Genet. 2006;43:722–728.

    CAS  Article  Google Scholar 

  17. 17.

    Gedge F, McDonald J, Phansalkar A, et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007;9:258–265.

    CAS  Article  Google Scholar 

  18. 18.

    Richards-Yutz J, Grant K, Chao EC, Walther SE, Ganguly A. Update on molecular diagnosis of hereditary hemorrhagic telangiectasia. Hum Genet. 2010;128:61–77.

    CAS  Article  Google Scholar 

  19. 19.

    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;79:335–344.

    CAS  Article  Google Scholar 

  20. 20.

    Gallione CJ, Richards JA, Letteboer TG, et al. SMAD4 mutations found in unselected HHT patients. J Med Genet. 2006;43:793–797.

    CAS  Article  Google Scholar 

  21. 21.

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

    CAS  Article  Google Scholar 

  22. 22.

    Damjanovich K, Langa C, Blanco FJ, et al. 5’UTR mutations of ENG cause hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2011;6:85.

    Article  Google Scholar 

  23. 23.

    Wooderchak-Donahue WL, McDonald J, Farrell A, et al. Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in hereditary haemorrhagic telangiectasia. J Med Genet. 2018;55:824–830.

    CAS  Article  Google Scholar 

  24. 24.

    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;17:405–424.

    Article  Google Scholar 

  25. 25.

    Bayrak-Toydemir P, McDonald J, Mao R, et al. Likelihood ratios to assess genetic evidence for clinical significance of uncertain variants: hereditary hemorrhagic telangiectasia as a model. Exp Mol Pathol. 2008;85:45–49.

    CAS  Article  Google Scholar 

  26. 26.

    Olivieri C, Pagella F, Semino L, et al. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet. 2007;52:820–829.

    CAS  Article  Google Scholar 

  27. 27.

    Finn RD, Attwood TK, Babbitt PC, et al. InterPro in 2017-beyond protein family and domain annotations. Nucleic Acids Res. 2017;45(D1):D190–D199.

    CAS  Article  Google Scholar 

  28. 28.

    Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–249.

    CAS  Article  Google Scholar 

  29. 29.

    Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073–1081.

    CAS  Article  Google Scholar 

  30. 30.

    Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 2010;20:110–121.

    CAS  Article  Google Scholar 

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Acknowledgements

We thank the patients for participating in this research. We thank members of the ARUP Molecular Genetics and Genomics Clinical Laboratories for assisting in the sequence analysis of these patients. We thank the ARUP Institute for Clinical and Experimental Pathology for supporting this work.

Author information

Affiliations

  1. Department of Radiology, University of Utah, Salt Lake City, UT, USA

    Jamie McDonald MS, LCGC

  2. Department of Pathology, University of Utah, Salt Lake City, UT, USA

    Jamie McDonald MS, LCGC, Pinar Bayrak-Toydemir MD, PhD & Whitney Wooderchak-Donahue PhD

  3. ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA

    Pinar Bayrak-Toydemir MD, PhD, Desiree DeMille PhD & Whitney Wooderchak-Donahue PhD

  4. Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA

    Kevin Whitehead MD

  5. Program in Molecular Medicine, University of Utah, Salt Lake City, UT, USA

    Kevin Whitehead MD

  6. George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT, USA

    Kevin Whitehead MD

Authors
  1. Jamie McDonald MS, LCGC
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  2. Pinar Bayrak-Toydemir MD, PhD
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  3. Desiree DeMille PhD
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  4. Whitney Wooderchak-Donahue PhD
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Correspondence to Jamie McDonald MS, LCGC.

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McDonald, J., Bayrak-Toydemir, P., DeMille, D. et al. Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2). Genet Med 22, 1201–1205 (2020). https://doi.org/10.1038/s41436-020-0775-8

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Keywords

  • HHT
  • Curaçao criteria
  • ACVRL1
  • ENG

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