Submission Details

ACTA2 was first reported in relation to autosomal dominant familial thoracic aortic aneurysm and dissection (FTAAD) in 2007 (Guo et al., PMID: 17994018). Since 2007, it has also been reported in relation to smooth muscle dysfunction syndrome and Moyamoya disease (PMIDs: 19409525, 20734336). Individuals with variants in ACTA2 can have variable features including, but not limited to, dysfunction of smooth muscle throughout the body manifesting with familial thoracic aortic aneurysms and dissections, coronary artery disease, early-onset atherosclerosis, patent ductus arteriosus, intestinal hypoperistalsis, hypotonic bladder, congenital mydriasis, livedo reticularis, pulmonary hypertension, and cerebrovascular disease resulting in transient ischemic attacks or strokes (PMIDs: 17994018, 29300374, 19409525, 20734336). Variants in ACTA2, notably R179H/C, have been associated with a characteristic brain malformation which includes anterior callosal hypoplasia, notching of the brainstem, and radial dysgyria in addition to characteristic twig-like branching of the cerebral arteries and anterior circulation steno-occlusive disease downstream of dilated cavernous carotid arteries (reviewed in PMID: 30300893; primary evidence in PMID: 34857515, 33199432, 30262641). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: Smooth Muscle Dysfunction Syndrome (OMIM: 613834), Familial Thoracic Aortic Aneurysm and Dissection (OMIM: 611788) and Moyamoya disease (OMIM: 614042).

Ten unique missense variants that have been reported in 17 probands across 4 publications (PMIDs: 17994018, 29300374, 19409525, 20734336) are included in this curation. Much of the literature links ACTA2-related SMDS solely to the R179 residue; however, new evidence has been reported on variants in other residues that also cause SMDS features. This residue has been associated with the most severe phenotypes and often a pediatric age of onset (PMID: 35567597). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity is reported to be dominant negative.

This gene-disease association is also supported by experimental evidence including biochemical function assays showing that contractile function disruption and smooth muscle cell (SMC) proliferation are consistent with the vascular phenotypes found in patients with ACTA2-related FTAAD (PMID: 17994018). The function of ACTA2 is consistent with that of MYH11 which has been known to cause TAAD and was given a definitive classification by the HTAAD GCEP (PMID: 17994018). Expression data shows that ACTA2 is highly expressed in relevant tissue: smooth muscle and the aorta (PMIDs: 23715323, 28940711). Guo et. al., 2009 (PMID: 19409525) also found that SMCs and myofibroblasts explanted from patients with heterozygous ACTA2 variants result in increased proliferation of smooth muscle cells, which was shown to result in reduction in the lumen diameter leading to occlusion of the arteries. Finally, ACTA2 knockout mouse models show decreased expression of ACTA2, increased aorta dilation, and reduced contractility of smooth muscle cells compared to WT groups (PMIDs: 15371786, 30233845).

In summary, ACTA2 is definitively associated with autosomal dominant multisystemic smooth muscle dysfunction syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification of ACTA2 for FTAAD was originally approved by the ClinGen Heritable Thoracic Aortic Aneurysm and Dissection Gene Curation Expert Panel on September 9, 2016. It was reevaluated on 1/24/2025 and expanded to include smooth muscle dysfunction syndrome and Moyamoya-like disease. As a result of this reevaluation, the classification did not change. This classification was approved by the ClinGen Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Disease GCEP on 1/24/2025 (SOP Version 11).