To describe characteristics of a family with congenital myopathy, variably-penetrant dilated cardiomyopathy, and a novel, likely pathogenic variant in ACTA1, c.81C>A (p.Asp27Glu).

ACTA1 encodes skeletal muscle alpha-actin, the primary actin isoform in human skeletal muscle, also expressed to a lesser degree in cardiac muscle. Mutations in ACTA1 are common in patients with congenital myopathies; however, associated cardiomyopathy is rare.

Retrospective chart review of the proband and 3 family members.

The proband was a 47-year-old Caucasian male of Ukrainian heritage. His mother (73), sister (40), and nephew (18) were similarly affected. All were hypotonic at birth, had delayed motor milestones, and presented with high-arched palate, elongated facies, and mild-moderate axial and proximal-predominant weakness. The proband had dilated cardiomyopathy with congestive heart failure and intraventricular conduction delay, his sister had dilated cardiomyopathy with left anterior fascicular block, his nephew had left ventricular dilatation with preserved function and normal conduction, and his mother had atrial fibrillation without structural heart disease. Biceps brachii biopsy in the proband demonstrated congenital fiber-type disproportion (CFTD), in addition to rare nemaline rods on electron microscopy. Next-generation sequencing identified a novel, likely pathogenic variant in ACTA1, c.81C>A (p.Asp27Glu), segregating in affected family members.  This missense variant is not present in population databases and affects a highly conserved amino acid. In silico models predicted a deleterious effect on protein structure and function (PolyPhen-2: probably damaging; SIFT: 0.0; MutationTaster: disease-causing).

This family expands the genotypic and phenotypic spectrum of ACTA1-related myopathies. The novel missense variant c.81C>A (p.Asp27Glu) associates with autosomal dominant congenital myopathy, CFTD, and variable, non-age-dependent penetrance of cardiac structural abnormalities along the spectrum of left ventricular dilatation and systolic dysfunction. Dilated cardiomyopathy and CFTD are rare in both isolation and combination in ACTA1-related myopathies. We emphasize that early cardiac surveillance is important in patients with ACTA1-related myopathies.