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

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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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.

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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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