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

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

Research output: Contribution to journalArticlepeer-review

Abstract

-The geographic isolation and homogeneous population of Iceland is ideally suited to ascertain clinical and genetic characteristics of hypertrophic cardiomyopathy (HCM) at the population level.
-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 HCM patients. 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 15(th) 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 vs. 49 years, p=0.001) and sustained more adverse events (15% vs. 2%, p=0.02) than mutation-negative patients. All-cause mortality for HCM patients was similar to an age-matched Icelandic population (Hazard Ratio 0.98, p=0.9). HCM-related mortality (0.78%/year) occurred at a mean age of 68 compared to 81 years for non-HCM related mortality (p=0.02).
-A founder MYBPC3 mutation that arose over 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.
Original languageEnglish
Pages (from-to)1158-1167
JournalCirculation
Volume130
Issue number14
DOIs
Publication statusPublished - 30 Jul 2014

Other keywords

  • Hjartasjúkdómar
  • Arfgengi
  • Cardiomyopathy, Hypertrophic/mortality*
  • Cardiomyopathy, Hypertrophic/genetics*
  • Carrier Proteins/genetics*
  • Iceland/epidemiology
  • Genetic Predisposition to Disease/genetics*
  • Genetic Predisposition to Disease/epidemiology*
  • Adolescent
  • Adult
  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Child
  • Child, Preschool
  • Female
  • Founder Effect*
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Phenotype
  • Prevalence
  • Young Adult

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