Jamie McDonald1,2, Pinar Bayrak-Toydemir3,4, Desiree DeMille4, Whitney Wooderchak-Donahue3,4, Kevin Whitehead5,6,7. 1. Department of Radiology, University of Utah, Salt Lake City, UT, USA. Jamie.mcdonald@hsc.utah.edu. 2. Department of Pathology, University of Utah, Salt Lake City, UT, USA. Jamie.mcdonald@hsc.utah.edu. 3. Department of Pathology, University of Utah, Salt Lake City, UT, USA. 4. ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA. 5. Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA. 6. Program in Molecular Medicine, University of Utah, Salt Lake City, UT, USA. 7. George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT, USA.
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.
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.
Authors: Alexandra Kilian; Giuseppe A Latino; Andrew J White; Dewi Clark; Murali M Chakinala; Felix Ratjen; Jamie McDonald; Kevin Whitehead; James R Gossage; Doris Lin; Katharine Henderson; Jeffrey Pollak; Justin P McWilliams; Helen Kim; Michael T Lawton; Marie E Faughnan Journal: J Clin Med Date: 2020-08-22 Impact factor: 4.241
Authors: Joshua Hodgson; Lidia Ruiz-Llorente; Jamie McDonald; Oliver Quarrell; Kelechi Ugonna; James Bentham; Rebecca Mason; Jennifer Martin; David Moore; Katie Bergstrom; Pinar Bayrak-Toydemir; Whitney Wooderchak-Donahue; Nicholas W Morrell; Robin Condliffe; Carmelo Bernabeu; Paul D Upton Journal: Mol Genet Genomic Med Date: 2021-04-09 Impact factor: 2.183