Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: founder mutations in ACVRL1 |
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| Authors: | K. Heimdal B. Dalhus O.K. Rødningen M. Kroken K. Eiklid S. Dheyauldeen T. Røysland R. Andersen M.A. Kulseth |
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| Affiliation: | 1. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway;2. Department for Medical Biochemistry, University of Oslo, Oslo, Norway;3. Department for Microbiology, Oslo University Hospital, Oslo, Norway;4. Department for Otorhinolaryngology, Oslo University Hospital, Oslo, Norway;5. Department for Otorhinolaryngology, Innlandet Hospital, Gj?vik, Norway;6. Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway |
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| 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. |
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| Keywords: | ACVRL1 ENG founder mutation mutation genetic testing hereditary hemorrhagic telangiectasia HHT Osler– Weber– Rendu |
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