Table 1:
Genes validated and proposed to predispose to heritable thoracic aortic disease (HTAD) in humans
| Risk associated with HTAD | Genes name | Protein | Inheritance | Associated syndrome‡ | OMIM | HI | Domain location for missense, inframe deletion/duplication | Pathways impacted |
|---|---|---|---|---|---|---|---|---|
| Definitive | ACTA2 | smooth muscle actin α2 | AD | Smooth muscle dysfunction syndrome | 613834 | No* | † | SMC contraction |
| COL3A1 | procollagen type III α1 | AD | Vascular Ehlers-Danlos syndrome | 130050 | Yes | Triple helical domain (disruptglycines) | ECM | |
| FBN1 | fibrillin-1 | AD | Marfan syndrome | 154700 | Yes | Mainly EGF-like domains (disruption cysteines and calcium binding) | ECM | |
| MYH11 | smooth muscle myosin heavy chain 11 | AD | 132900 | No* | Missense mutations and inframe deletions in coiled coil domain | SMC contraction | ||
| SMAD3 | mothers against decapentaplegic drosophila homolog 3 | AD | Loeys-Dietz syndrome 3 | 613795 | Yes | Mainly MH2 domain, but also MH1 domain | TGF-β | |
| TGFB2 | transforming growth factor β2 | AD | Loeys-Dietz syndrome 4 | 614816 | Yes | Furin cleavage site and cytokine domain | TGF-β | |
| TGFBR1 | transforming growth factor β receptor type I | AD | Loeys-Dietz syndrome 1 | 609192 | Yes | Intracellular kinase domain | TGF-β | |
| TGFBR2 | transforming growth factor β receptor type II | AD | Loeys-Dietz syndrome 2 | 610168 | Yes | Intracellular kinase domain | TGF-β | |
| MYLK | myosin light chain kinase | AD | 613780 | Yes | Kinase and calmodulin-binding domain | SMC contraction | ||
| Strong | LOX | lysyl oxydase | AD | Musculoskeletal manifestations of Marfan syndrome | 617168 | Yes | Catalytic domain | ECM |
| PRKG1 | protein kinase cGMP-dependent type 1 | AD | 615436 | No* | Onegain of function mutation, p.Arg177Gln | SMC contraction | ||
| Moderate | EFEMP2 | EGF containing fibulin-like extracellular matrix protein 2 (fibulin-4) | AR | Cutis laxa type 1B syndrome | 614437 | ECM | ||
| Limited | ELN | elastin | AD | Cutis Laxa syndrome | 123700 | ECM | ||
| FBN2 | fibrillin 2 | AD | Congenital contractural arachnodactyly | 121050 | EGF-like domain | ECM | ||
| FLNA | filamin A | X-linked Recessive | Cardiac valvular dysplasia | 314400 | SMC contraction | |||
| NOTCH1 | notch 1 | AD | 109730 | EGF-like domain | ||||
| SLC2A10 | solute carrier family 2 member 10 | AR | Arterial tortuosity syndrome | 208050 | ||||
| SMAD4 | mothers against decapentaplegic drosophila homolog 4 | AD | Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome | 175050 | Yes | Mainly MH2 domain | TGF-β | |
| SKI | SKI proto-oncogene | AD | Shprintzen-Goldberg syndrome | 182212 | SMAD-binding domain | TGF-β | ||
| Uncertain (recent reported genes) | BGN | biglycan | X-linked Recessive | Musculoskeletal manifestations of Marfan syndrome | 300989 | ECM | ||
| FOXE3 | forkhead box E3 | AD | 617349 | Forkhead DNA-binding domain | ||||
| HCN4 | hyperpolarization activated cyclic nucleotide-gated potassium channel 4 | AD | 163800 | |||||
| MAT2A | methionine adenosyltransferase II α | AD | 607086 | Catalytic domain | ||||
| MFAP5 | microfibrillar associated protein 5 | AD | Musculoskeletal manifestations of Marfan syndrome | 616166 | Yes | N-terminal domain | ECM | |
| SMAD2 | mothers against decapentaplegic drosophila homolog 2 | AD | MH2 domain | TGF-β | ||||
| TGFB3 | transforming growth factor β3 | AD | Loeys-Dietz syndrome 5 | 615582 | Furin cleavage site and cytokine domains | TGF-β | ||
| LTBP3 | latent transforming growth factor β binding protein 3 | AR | Dental anomalies and short stature syndrome | 601216 | EGF-like domain | ECM and TGF-β | ||
| ARIH1 | ariadne drosophila homolog 1 | AD | Yes | Glycine-rich domain |
Footnotes: HI: Haploinsufficiency in the gene can cause disease, AD: Autosomal Dominant, AR: Autosomal Recessive.
Based on current data,
pathogenic variants are found throughout the gene,
Individuals can have pathogenic variants in these genes and may have no syndromic features but have thoracic aortic disease or other vascular diseases.
Based on the ClinGen Aortopathy Working Group classification,20 “Definitive” and “Strong” genes are established to predispose to heritable thoracic aortic disease. “Moderate” and “Limited” genes are potentially important in terms of proper diagnosis in an individual with thoracic aortic enlargement but these genes do not carry significant risk for progression to acute aortic dissections. “Uncertain” category indicates recently published genes for which the data are limited and no categorization is possible until additional data are available.