BabyScreen+ newborn screening

Gene: ACTA2

Green List (high evidence)

Clinical Evidence
Youngest dissection 6mo in monoallelic
Fetal and Neonatal onset in Biallelic
Spontaneous dissection in normal sized aorta
Ao event - 36% at median age of 14, 100% by 25yo
Dissections have been reported in children without dilatation
And in those with dilatation <4cm
In a family with a dissection, if we have a pre-dissection diameter we recommend planned intervention at 0.5cm less
Suggest consideration of prophylactic replacement at 3.5cm or prior to 18yo
All individuals should be on prophylaxis after discussion with family

Positive Family history of Dissection increases risk of dissection in affected family members
- Higher no of events, younger age at diagnosis, shorter duration of dilatation prior to dissection and higher annual probability of dissection
Aortic Aneurysms Present or Absent

Ma,W.G.; Chou, A.S.; Mok, S.C.M.; Ziganshin, B.A.; Charilaou, P.; Zafar, M.A.; Sieller, R.S.; Tranquilli, M.;
Rizzo, J.A.; Elefteriades, J.A. Positive family history of aortic dissection dramatically increases dissection risk
in family members. Int. J. Cardiol. 2017, 240, 132–137. [CrossRef] [PubMed]


Regalado ES, Mellor-Crummey L, De Backer J, Braverman AC, Ades L, Benedict S, Bradley TJ, Brickner ME, Chatfield KC, Child A, Feist C, Holmes KW, Iannucci G, Lorenz B, Mark P, Morisaki T, Morisaki H, Morris SA, Mitchell AL, Ostergaard JR, Richer J, Sallee D, Shalhub S, Tekin M; Montalcino Aortic Consortium, Estrera A, Musolino P, Yetman A, Pyeritz R, Milewicz DM. Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations. Genet Med. 2018 Oct;20(10):1206-1215. doi: 10.1038/gim.2017.245. Epub 2018 Jan 4. PMID: 29300374; PMCID: PMC6034999.

Brownstein, A.J.; Kostiuk, V.; Ziganshin, B.A.; Zafar, M.A.; Kuivaniemi, H.; Body, S.C.; Bale, A.E.;
Elefteriades, J.A. Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2018 Update and
Clinical Implications. Aorta 2018, 6, 13–20.

Congenital mydriasis and related pupillary abnormalites at birth and presented in infancy with a patent ductus arteriosus or aorto-pulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary or stroke complications, or unknown causes.

Visceral Myopathy/MMIHS-alleilic features (ACTG2/CHRM3/LMOD1/MYH11)
Hypotonic bladder, cryptorchidism, malrotation & hypoperistalsis of the gut 1; prune-belly sequence may be associated. 2Thoracic aortic aneurysms & aortic dissections, PDA, stenosis & dilatation of cerebral vessels, mydriasis, periventricular white matter hyperintensities on MRI; pulmonary hypertension

Milewicz DM, Østergaard JR, Ala-Kokko LM, et al. De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. Am J Med Genet A. 2010;152A(10):2437-2443. doi:10.1002/ajmg.a.33657

Created: 15 Feb 2023, 3:58 a.m. | Last Modified: 15 Feb 2023, 3:58 a.m.

Panel Version: 0.1865

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Mode of pathogenicity
Other

Green List (high evidence)

Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance:
A study of 277 individuals with ACTA2 pathogenic variants indicated that 48% had an aortic event defined as either an aortic dissection (42%) or surgical repair of aortic aneurysms (6%). An additional 9% had an aneurysm that did not require repair. The overall cumulative risk of an aortic event by age 86 was estimated as 76% (95% CI: 64-86%).

Created: 30 Dec 2022, 2:04 a.m. | Last Modified: 30 Dec 2022, 2:04 a.m.

Panel Version: 0.1776

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Aortic aneurysm, familial thoracic 6, MIM# 611788