This Article Full Text Full Text (PDF) Supplemental Material Purchase Article View Shopping Cart Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gedge, F. Articles by Bayrak-Toydemir, P. Search for Related Content PubMed Articles by Gedge, F. Articles by Bayrak-Toydemir, P.

JMD 2007, Vol. 9, No. 2
Copyright © 2007 American Society for Investigative Pathology & Association for Molecular Pathology

Clinical and Analytical Sensitivities in Hereditary Hemorrhagic Telangiectasia Testing and a Report of de Novo Mutations

Friederike Gedge^*, Jamie McDonald^*, Amit Phansalkar^*, Lan-Szu Chou^*, Fernanda Calderon^*, Rong Mao^*, Elaine Lyon^* and Pinar Bayrak-Toydemir^*

From the Associated Regional and University Pathologists, * Institute of Clinical and Experimental Pathology, Salt Lake City; and the Departments of Radiology and Pathology, University of Utah, Salt Lake City, Utah

Hereditary hemorrhagic telangiectasia is a vascular dysplasia with variable onset and expression. Through identification of a mutation in a proband, mutation testing can be offered to family members. Mutation carriers can receive medical surveillance and treatment before potentially fatal complications arise. In this study, we assessed the significance of clinical evaluations as part of hereditary hemorrhagic telangiectasia diagnostic testing to determine the clinical sensitivity of molecular testing and to report novel mutations. Based on reported clinical symptoms, we classified 142 consecutive cases as affected, suspected, or unlikely affected. We performed temperature gradient capillary electrophoresis and full gene sequencing of both ACVRL1 and ENG genes. We then compared the mutation detection rates between these groups, categorizing sequence variants as mutations, variants of uncertain significance (VUS), or known polymorphisms. Our mutation and VUS detection rate in affected individuals was 74% and 16% in the suspected/unlikely affected group. Sixty-one percent of the mutations and all VUS were novel. The mutation detection rate for temperature gradient capillary electrophoresis was 97%. Our results suggest that a careful clinical evaluation increases the mutation detection rate. We have confirmed the occurrence of de novo mutations in three patients. Our results also show that temperature gradient capillary electrophoresis is an efficient mutation screening method.