Introduction to TAAD (GAD)
Thoracic aortic disorders almost exclusively include thoracic aortic aneurysms and dissections (TAAD) triggered by genetic predispositions. Inherited TAAD is termed heritable thoracic aortic disorder/disease, HTAD*.
Up to 20% of individuals with TAAD have a family history of (inherited) TAAD but do not have typical, or any features of a known syndrome.
Families with autosomal dominant inheritance of TAAD without typical syndromic features are considered to have a familial TAAD or FTAAD*. For the majority of FTAAD families, decreased penetrance for TAAD occurs primarily in women.
TAAD is mostly inherited in an autosomal dominant manner with reduced penetrance
and variable expressivity.
The variable expressivity includes the age of disease onset, type of TAAD presentation/features and whether there is a risk of other cardiovascular conditions.
Other cardiovascular conditions could be: aneurysms and dissections of other large and small arteries, presence of congenital heart defects: PDA- patent ductus arteriosus and BAV- bicuspid aortic valve, and early onset stroke or coronary artery disease.
TAAD is a complication in genetic syndromes like Marfan (MFS), Loeys-Dietz (LDS) and Multisystem Smooth Muscle Dysfunction Syndrome (ACTA2), and in apparently non- syndromic FTAAD/GAD (MYLK, MYH11, PRKG1, MAT2A).
It is important to understand that the lines between syndromic and familial predisposition for TAAD, for the most of the causative genes, are not distinct. Most of the syndromic TAAD causative genes can also lead to autosomal dominant inheritance of TAAD without any syndromic features (FBN1, MFAP5, TGFBR1, TGFBR2, SMAD3, TGFB2 and ACTA2). A family with inherited TAAD can have the spectrum of syndromic to non-syndromic features among the affected family members.
Therefore, it is important to remember that syndromic features are NOT always reliable for identifying at risk individuals, even if the probant has the classic features of that syndrome.
In addition to causing TAAD, gene mutations along the same or different pathways, may have the same overlapping non-aortic features (e.g. marfanoid skeletal features in ECM and TGFB pathways)
Mutations of 12 genes have been discovered to lead to heritable TAAD. The known genes for autosomal dominant inheritance of FTAAD are classified based on the molecular pathway the mutated gene is known to disrupt:
Extra cellular matrix (ECM): FBN1, MFAP5
Transforming Growth factor beta (TGFB) signaling: TGFBR1, TGFBR2, TGFB2, SMAD3, TGFB3
Smooth Muscle cell contractility: ACTA2, MYH11, MYLK, PRKG1
Unknown cellular pathway: MAT2A
*GADA Canada groups HTAD and FTAAD into one cluster called: genetic aortic disorders, or GAD.