title: Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: founder mutations in ACVRL1.
abstract: Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is an autosomal dominant inherited disease defined by the presence of epistaxis and mucocutaneous telangiectasias and arteriovenous malformations (AVMs) in internal organs. In most families (~85%), HHT is caused by mutations in the ENG (HHT1) or the ACVRL1 (HHT2) genes. Here, we report the results of genetic testing of 113 Norwegian families with suspected or definite HHT. Variants in ENG and ACVRL1 were found in 105 families (42 ENG, 63 ACVRL1), including six novel variants of uncertain pathogenic significance. Mutation types were similar to previous reports with more missense variants in ACVRL1 and more nonsense, frameshift and splice-site mutations in ENG. Thirty-two variants were novel in this study. The preponderance of ACVRL1 mutations was due to founder mutations, specifically, c.830C>A (p.Thr277Lys), which was found in 24 families from the same geographical area of Norway. We discuss the importance of founder mutations and present a thorough evaluation of missense and splice-site variants.
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: K
authors.identifier: http://orcid.org/0000-0002-8911-3508
authors.initials: K
authors.lastname: Heimdal
authors.affiliation: Department for Medical Biochemistry, University of Oslo, Oslo, Norway.|Department for Microbiology, Oslo University Hospital, Oslo, Norway.
authors.forename: B
authors.initials: B
authors.lastname: Dalhus
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: O K
authors.initials: OK
authors.lastname: Rødningen
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Kroken
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: K
authors.initials: K
authors.lastname: Eiklid
authors.affiliation: Department for Otorhinolaryngology, Oslo University Hospital, Oslo, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Dheyauldeen
authors.affiliation: Department for Otorhinolaryngology, Oslo University Hospital, Oslo, Norway.|Department for Otorhinolaryngology, Innlandet Hospital, Gjøvik, Norway.
authors.forename: T
authors.initials: T
authors.lastname: Røysland
authors.affiliation: Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.
authors.forename: R
authors.initials: R
authors.lastname: Andersen
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: M A
authors.initials: MA
authors.lastname: Kulseth
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics*; D015703:Antigens, CD / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D000071063:Endoglin; D005190:Family; D018703:Founder Effect; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009664:Norway; D011956:Receptors, Cell Surface / Q000235:genetics; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics*
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II
keywords: ACVRL1; ENG; HHT; Osler-Weber-Rendu; founder mutation; genetic testing; hereditary hemorrhagic telangiectasia; mutation