Mutations in Alpha-Actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis

Christine Chiu, Richard D. Bagnall, Jodie Ingles, Laura Yeates, Marina Kennerson, Jennifer A. Donald, Mika Jormakka, Joanne M. Lind, Christopher Semsarian*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    154 Citations (Scopus)


    Objectives: This study describes a genome-wide linkage analysis of a large family with clinically heterogeneous hypertrophic cardiomyopathy (HCM). Background: Familial HCM is a disorder characterized by genetic heterogeneity. In as many as 50% of HCM cases, the genetic cause remains unknown, suggesting that other genes may be involved. Methods: Clinical evaluation, including clinical history, physical examination, electrocardiography, and 2-dimensional echocardiography, was performed, and blood was collected from family members (n = 23) for deoxyribonucleic acid analysis. The family was genotyped with markers from the 10-cM AB PRISM Human Linkage mapping set (Applied Biosystems, Foster City, California), and 2-point linkage analysis was performed. Results: Affected family members showed marked clinical diversity, ranging from asymptomatic individuals to those with syncope, heart failure, and premature sudden death. The disease locus for this family was mapped to chromosome 1q42.2-q43, near the marker D1S2850 (logarithm of odds ratio = 2.82, θ = 0). A missense mutation, Ala119Thr, in the alpha-actinin-2 (ACTN2) gene was identified that segregated with disease in the family. An additional 297 HCM probands were screened for mutations in the ACTN2 gene using high-resolution melt analysis. Three causative ACTN2 mutations, Thr495Met, Glu583Ala, and Glu628Gly, were identified in an additional 4 families (total 1.7%) with HCM. Conclusions: This is the first genome-wide linkage analysis that shows mutations in ACTN2 cause HCM. Mutations in genes encoding Z-disk proteins account for a small but significant proportion of genotyped HCM families.

    Original languageEnglish
    Pages (from-to)1127-1135
    Number of pages9
    JournalJournal of the American College of Cardiology
    Issue number11
    Publication statusPublished - 16 Mar 2010


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