ACTC1 Variants Result in Isolated and Syndromic Cardiac Phenotypes.

Abstract

Individuals carrying pathogenic variants in ACTC1 present with several cardiac phenotypes, including hypertrophic cardiomyopathy, dilated cardiomyopathy, and left ventricular noncompaction cardiomyopathy. In the current work, we expand the clinical and genetic spectrum of phenotypes caused by ACTC1 genetic variants by describing two individuals with heterozygous variants involving residues Gly57 or Glu101. These individuals presented with facial dysmorphism, short stature, and skeletal anomalies in addition to hypertrophic and left ventricular noncompaction cardiomyopathies. Protein structure analysis showed these variants alter the ATP binding or putative protein-protein interactions, while in vivo zebrafish analysis validated the pathogenicity of these ACTC1 variants and their impact on the development of the cranial tissues. Combined with recent reports of other individuals with ACTC1 variants and extracardiac phenotypes, this study provides further evidence of the extensive molecular and clinical diversity related to ACTC1.