Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genomewide analysis

Background: Familial hypertrophic cardiomyopathy (HCM) is a disorder characterised by
genetic heterogeneity. In up to 50% of HCM cases, the genetic cause remains unknown,
suggesting other genes may be involved. This study describes a genome-wide linkage analysis
of a large family with clinically heterogeneous HCM. Methods and Results: Clinical evaluation,
including clinical history, physical examination, ECG, and 2D echocardiogram, was performed,
and blood collected from family members (n=23) for DNA analysis. Affected family members
showed marked clinical diversity, ranging from asymptomatic individuals, to those with
syncope, heart failure, and premature sudden death. The family was genotyped with markers
from the 10cM AB PRISM Human Linkage mapping set, and two-point linkage analysis was
performed. LOD scores were calculated for each marker assuming an autosomal dominant
mode of inheritance for disease with a penetrance of 95%, and a disease allele frequency of
0.001. The disease locus for this family was mapped to chromosome 1q42.2-q43, near the
marker D1S2850 (LOD = 2.82, θ=0). A missense mutation, Ala119Thr, in the α-actinin-2
(ACTN2) gene was identified that segregated with disease in the family. Predictive modelling
indicates this mutation, which lies in a critical actin-binding domain in the encoded ACTN2
protein within the Z-disc region, may affect the actin-binding interface and alter the
actin-binding affinity of ACTN2. 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 definitive genome-wide linkage analysis that shows
mutations in ACTN2 cause HCM. Mutations in genes encoding Z-disc proteins account for a
small but significant proportion of genotyped HCM families.