title: Nationwide study on hypertrophic cardiomyopathy in Iceland: evidence of a MYBPC3 founder mutation.
abstract: BACKGROUND
  The geographic isolation and homogeneous population of Iceland are ideally suited to ascertain clinical and genetic characteristics of hypertrophic cardiomyopathy (HCM) at the population level.
  
  
  RESULTS
  Medical records and cardiac imaging studies obtained between 1997 and 2010 were reviewed to identify Icelandic patients with HCM. Surviving patients were recruited for clinical and genetic studies. A previously identified Icelandic mutation, MYBPC3 c.927-2A>G, was genotyped, and mutation-negative samples were sequenced for HCM genes and other hypertrophic genes. Record review identified 180 patients with HCM. Genetic analyses of 151 patients defined pathogenic mutations in 101 (67%), including MYBPC3 c.927-2A>G (88 patients, 58%), 4 other MYBPC3 or MYH7 mutations (5 patients, 3.3%), and 2 GLA mutations (8 patients, 5.3%). Haplotype and genetic genealogical data defined MYBPC3 c.927-2A>G as a founder mutation, introduced into the Icelandic population in the 15th century, with a current population prevalence of 0.36%. MYBPC3 c.927-2A>G mutation carriers exhibited phenotypic diversity but were younger at diagnosis (42 versus 49 years; P=0.001) and sustained more adverse events (15% versus 2%; P=0.02) than mutation-negative patients. All-cause mortality for patients with HCM was similar to that of an age-matched Icelandic population (hazard ratio, 0.98; P=0.9). HCM-related mortality (0.78%/y) occurred at a mean age of 68 compared with 81 years for non-HCM-related mortality (P=0.02).
  
  
  CONCLUSIONS
  A founder MYBPC3 mutation that arose >550 years ago is the predominant cause of HCM in Iceland. The MYBPC3 c.927-2A>G mutation is associated with low adverse event rates but earlier cardiovascular mortality, illustrating the impact of genotype on outcomes in HCM.
authors: From Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (B.A., R.D.); Faculty of Medicine (B.A., K.S., G.T.G.) and School of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., S.R.D., E.M., B.M., J.G.S., C.E.S.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); deCODE Genetics, Reykjavik, Iceland (D.F.G., H.H., K.S.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Akureyri Hospital, Akureyri, Iceland (G.T.G.). berglind.ba@gmail.com.
authors: Berglind
authors: B
authors: Adalsteinsdottir
authors: From Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (B.A., R.D.); Faculty of Medicine (B.A., K.S., G.T.G.) and School of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., S.R.D., E.M., B.M., J.G.S., C.E.S.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); deCODE Genetics, Reykjavik, Iceland (D.F.G., H.H., K.S.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Akureyri Hospital, Akureyri, Iceland (G.T.G.).
authors: Polakit
authors: P
authors: Teekakirikul
authors: From Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (B.A., R.D.); Faculty of Medicine (B.A., K.S., G.T.G.) and School of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., S.R.D., E.M., B.M., J.G.S., C.E.S.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); deCODE Genetics, Reykjavik, Iceland (D.F.G., H.H., K.S.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Akureyri Hospital, Akureyri, Iceland (G.T.G.).
authors: Barry J
authors: BJ
authors: Maron
authors: From Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (B.A., R.D.); Faculty of Medicine (B.A., K.S., G.T.G.) and School of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., S.R.D., E.M., B.M., J.G.S., C.E.S.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); deCODE Genetics, Reykjavik, Iceland (D.F.G., H.H., K.S.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Akureyri Hospital, Akureyri, Iceland (G.T.G.).
authors: Michael A
authors: MA
authors: Burke
authors: From Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (B.A., R.D.); Faculty of Medicine (B.A., K.S., G.T.G.) and School of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., S.R.D., E.M., B.M., J.G.S., C.E.S.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); deCODE Genetics, Reykjavik, Iceland (D.F.G., H.H., K.S.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Akureyri Hospital, Akureyri, Iceland (G.T.G.).
authors: Daniel F
authors: DF
authors: Gudbjartsson
authors: From Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (B.A., R.D.); Faculty of Medicine (B.A., K.S., G.T.G.) and School of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., S.R.D., E.M., B.M., J.G.S., C.E.S.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); deCODE Genetics, Reykjavik, Iceland (D.F.G., H.H., K.S.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Akureyri Hospital, Akureyri, Iceland (G.T.G.).
authors: Hilma
authors: H
authors: Holm
authors: From Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (B.A., R.D.); Faculty of Medicine (B.A., K.S., G.T.G.) and School of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., S.R.D., E.M., B.M., J.G.S., C.E.S.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); deCODE Genetics, Reykjavik, Iceland (D.F.G., H.H., K.S.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Akureyri Hospital, Akureyri, Iceland (G.T.G.).
authors: Kari
authors: K
authors: Stefansson
authors: From Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (B.A., R.D.); Faculty of Medicine (B.A., K.S., G.T.G.) and School of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., S.R.D., E.M., B.M., J.G.S., C.E.S.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); deCODE Genetics, Reykjavik, Iceland (D.F.G., H.H., K.S.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Akureyri Hospital, Akureyri, Iceland (G.T.G.).
authors: Steven R
authors: SR
authors: DePalma
authors: From Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (B.A., R.D.); Faculty of Medicine (B.A., K.S., G.T.G.) and School of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., S.R.D., E.M., B.M., J.G.S., C.E.S.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); deCODE Genetics, Reykjavik, Iceland (D.F.G., H.H., K.S.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Akureyri Hospital, Akureyri, Iceland (G.T.G.).
authors: Erica
authors: E
authors: Mazaika
authors: From Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (B.A., R.D.); Faculty of Medicine (B.A., K.S., G.T.G.) and School of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., S.R.D., E.M., B.M., J.G.S., C.E.S.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); deCODE Genetics, Reykjavik, Iceland (D.F.G., H.H., K.S.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Akureyri Hospital, Akureyri, Iceland (G.T.G.).
authors: Barbara
authors: B
authors: McDonough
authors: From Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (B.A., R.D.); Faculty of Medicine (B.A., K.S., G.T.G.) and School of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., S.R.D., E.M., B.M., J.G.S., C.E.S.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); deCODE Genetics, Reykjavik, Iceland (D.F.G., H.H., K.S.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Akureyri Hospital, Akureyri, Iceland (G.T.G.).
authors: Ragnar
authors: R
authors: Danielsen
authors: From Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (B.A., R.D.); Faculty of Medicine (B.A., K.S., G.T.G.) and School of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., S.R.D., E.M., B.M., J.G.S., C.E.S.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); deCODE Genetics, Reykjavik, Iceland (D.F.G., H.H., K.S.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Akureyri Hospital, Akureyri, Iceland (G.T.G.).
authors: Jonathan G
authors: JG
authors: Seidman
authors: From Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (B.A., R.D.); Faculty of Medicine (B.A., K.S., G.T.G.) and School of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., S.R.D., E.M., B.M., J.G.S., C.E.S.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); deCODE Genetics, Reykjavik, Iceland (D.F.G., H.H., K.S.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Akureyri Hospital, Akureyri, Iceland (G.T.G.).
authors: Christine E
authors: CE
authors: Seidman
authors: From Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (B.A., R.D.); Faculty of Medicine (B.A., K.S., G.T.G.) and School of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., S.R.D., E.M., B.M., J.G.S., C.E.S.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); deCODE Genetics, Reykjavik, Iceland (D.F.G., H.H., K.S.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Akureyri Hospital, Akureyri, Iceland (G.T.G.).
authors: Gunnar T
authors: GT
authors: Gunnarsson
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000401:mortality*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007055:Iceland / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D015995:Prevalence; D055815:Young Adult; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C
keywords: cardiomyopathies; genes; genetics; hypertrophy