title: Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis.
abstract: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by a unique pattern of telangiectasia and arteriovenous malformations (AVMs). Mutations in one of two genes (ENG and ACVRL1) cause approximately 85% of cases. Genetic testing impacts clinical management because genotype/phenotype correlations exist, and early preventive screening for internal AVMs is recommended in affected individuals prior to the age at which a diagnosis can typically be made based on clinical criteria. We report 383 consecutive cases in which sequencing and large deletion/duplication analysis were performed simultaneously for endoglin (ENG) and activin-like receptor kinase 1 (ACVRL1). We report the first case of mosaicism in an affected individual and 61 novel mutations. We discuss the potential benefits of a diagnostic testing approach for HHT whereby ENG and ACVRL1 are analyzed simultaneously by sequencing and a method which detects large deletion/duplications, rather than by a sequential or reflex testing protocol. We report a case in which a deletion would probably have been missed if large deletion/duplication analysis was performed only if a suspected pathogenic mutation was not first identified by sequencing.
authors.affiliation: Department of Radiology, HHT Center Department of Pathology, University of Utah, Salt Lake City, UT 84132, USA. jamie.mcdonald@hsc.utah.edu
authors.forename: J
authors.initials: J
authors.lastname: McDonald
authors.forename: K
authors.initials: K
authors.lastname: Damjanovich
authors.forename: A
authors.initials: A
authors.lastname: Millson
authors.forename: W
authors.initials: W
authors.lastname: Wooderchak
authors.forename: J M
authors.initials: JM
authors.lastname: Chibuk
authors.forename: D A
authors.initials: DA
authors.lastname: Stevenson
authors.forename: F
authors.initials: F
authors.lastname: Gedge
authors.forename: P
authors.initials: P
authors.lastname: Bayrak-Toydemir
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics*; D015703:Antigens, CD / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D000071063:Endoglin; D005091:Exons / Q000235:genetics; D016368:Frameshift Mutation; D020440:Gene Duplication; D006801:Humans; D009030:Mosaicism; D009154:Mutation; D020125:Mutation, Missense; D022821:RNA Splice Sites / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D017384:Sequence Deletion; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000175:diagnosis / Q000235:genetics*
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D022821:RNA Splice Sites; D011956:Receptors, Cell Surface; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II