Nationwide Study on Hypertrophic Cardiomyopathy in Iceland Evidence of a MYBPC3 Founder Mutation

作者：Adalsteinsdottir Berglind^*; Teekakirikul Polakit; Maron Barry J; Burke Michael A; Gudbjartsson Daniel F; Holm Hilma; Stefansson Kari; DePalma Steven R; Mazaika Erica; McDonough Barbara; Danielsen Ragnar; Seidman Jonathan G; Seidman Christine E; Gunnarsson Gunnar T

来源：Circulation, 2014, 130(14): 1158-1167.

DOI：10.1161/CIRCULATIONAHA.114.011207

• cardiomyopathies
• genes
• genetics
• hypertrophy

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. %26lt;br%26gt;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%26gt;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%26gt;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%26gt;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%26gt;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). %26lt;br%26gt;Conclusions-A founder MYBPC3 mutation that arose %26gt;550 years ago is the predominant cause of HCM in Iceland. The MYBPC3 c.927-2A%26gt;G mutation is associated with low adverse event rates but earlier cardiovascular mortality, illustrating the impact of genotype on outcomes in HCM.

• 出版日期2014-9-30