Berglind Adalsteinsdottir1, Polakit Teekakirikul2, Barry J Maron2, Michael A Burke2, Daniel F Gudbjartsson2, Hilma Holm2, Kari Stefansson2, Steven R DePalma2, Erica Mazaika2, Barbara McDonough2, Ragnar Danielsen2, Jonathan G Seidman2, Christine E Seidman2, Gunnar T Gunnarsson2. 1. 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. 2. 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.).
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. METHODS AND 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.
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. METHODS AND 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: Christopher N Toepfer; Hiroko Wakimoto; Amanda C Garfinkel; Barbara McDonough; Dan Liao; Jianming Jiang; Angela C Tai; Joshua M Gorham; Ida G Lunde; Mingyue Lun; Thomas L Lynch; James W McNamara; Sakthivel Sadayappan; Charles S Redwood; Hugh C Watkins; Jonathan G Seidman; Christine E Seidman Journal: Sci Transl Med Date: 2019-01-23 Impact factor: 17.956
Authors: Diederik W D Kuster; Thomas L Lynch; David Y Barefield; Mayandi Sivaguru; Gina Kuffel; Michael J Zilliox; Kyoung Hwan Lee; Roger Craig; Rajasekaran Namakkal-Soorappan; Sakthivel Sadayappan Journal: Cardiovasc Res Date: 2019-12-01 Impact factor: 10.787
Authors: Christopher A Koczor; Earl Fields; Mark J Jedrzejczak; Zhe Jiao; Tomika Ludaway; Rodney Russ; Joan Shang; Rebecca A Torres; William Lewis Journal: Toxicol Appl Pharmacol Date: 2015-08-22 Impact factor: 4.219
Authors: Yiting Fan; Tsz-Ngai Chan; Josie T Y Chow; Kevin K H Kam; Wai-Kin Chi; Joseph Y S Chan; Erik Fung; Mabel M P Tong; Jeffery K T Wong; Paul C L Choi; David K H Chan; Bun Sheng; Alex Pui-Wai Lee Journal: J Clin Med Date: 2021-05-17 Impact factor: 4.241