Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis.
OBJECTIVE
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, theta = 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.
Chiu
Christine
C
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Newtown, Australia.
Bagnall
Richard D
RD
Ingles
Jodie
J
Yeates
Laura
L
Kennerson
Marina
M
Donald
Jennifer A
JA
Jormakka
Mika
M
Lind
Joanne M
JM
Semsarian
Christopher
C
D000185:Actinin / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000000981:diagnostic imaging / Q000235:genetics*; D002648:Child; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D014463:Ultrasonography
C401401:ACTN2 protein, human; D000185:Actinin