Nationwide Study on Hypertrophic Cardiomyopathy in Iceland

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.

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

“…Several studies have previously demonstrated an increased risk of cardiac death in G+ versus G− HCM, [22][23][24] including studies of MYBPC3 founder mutations. 25,26 G− probands in this study were older and more symptomatic most likely related to LVOT obstruction and diastolic dysfunction. Possibly, G− HCM represents a separate disease with a different pathophysiology.…”

Next generation sequencing‐based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies

“…One example for this phenomenon is the GLA gene (Adalsteinsdottir et al. 2014; Alfares et al. 2015), which was traditionally tested only in patients with clinical diagnosis of Fabry disease, a lysosomal storage disorder that involves acroparesthesias, angiokeratomas, proteinuria, and cardiomyopathy (Germain 2010).…”

“…Inclusion of GLA in NGS panels revealed a larger than expected fraction of pathogenic GLA variants among individuals with apparently nonsyndromic HCM (Adalsteinsdottir et al. 2014; Alfares et al. 2015).…”

A Hypertrophic Cardiomyopathy-associated MYBPC3 Mutation Common in Populations of South Asian Descent Causes Contractile Dysfunction

“…To date, ϳ200 individual mutations in MYBPC3 have been identified, with the prevalence of individual mutations being low (6). Notable exceptions to this limited distribution of individual mutations can be found, including, for example, the 2373insG founder mutation, which is responsible for almost 25% of all HCM mutations in The Netherlands (40), or the recently described c.927-2AϾG founder mutation that occurs in almost 60% of Icelandic HCM patients (41). However, the most prevalent HCM-associated mutation is the 25-bp deletion mutation, which is estimated to occur in 55 million people worldwide (19).…”