Aortic Aneurysm

A(z) condition ismertetése

A localized, pathological dilatation of the aorta caused by a weakening of its wall, posing a risk of rupture. Around 20-30% of incidents are related to hereditary predisposition.

Heritable thoracic aortic disease encompasses a group of conditions predisposing to thoracic aortic aneurysm and dissection (TAAD), a life-threatening emergency where the aortic wall tears and causes massive bleeding. Approximately 20% of thoracic aortic aneurysms have a familial basis. FBN1 variants cause Marfan syndrome (prevalence approximately 1 in 5,000), which affects the aorta, eyes, and skeleton. TGFBR1 variants cause Loeys-Dietz syndrome, characterized by aggressive early-onset aortic disease, craniofacial features, and tissue friability. MYH11 variants cause familial non-syndromic TAAD, often with patent ductus arteriosus. All three follow autosomal dominant inheritance. Aortic dissection can occur without warning at aortic diameters considered safe in the general population, particularly in Loeys-Dietz syndrome, where aggressive aortic dilation and dissection can occur at relatively small aortic diameters.

FBN1 encodes fibrillin-1, a major structural component of extracellular matrix microfibrils; pathogenic variants weaken connective tissue and dysregulate transforming growth factor beta (TGF-β) signaling, causing progressive aortic root dilation. Over 3,000 FBN1 variants have been catalogued. TGFBR1 encodes a TGF-β type I receptor; loss-of-function variants paradoxically increase TGF-β signaling in the aortic wall, driving more aggressive aneurysm formation. MYH11 encodes smooth muscle myosin heavy chain; variants impair vascular smooth muscle cell contraction, compromising aortic wall integrity. Eleven genes total have confirmed high-penetrance TAAD risk, but three (FBN1, TGFBR1, and MYH11) account for the majority of heritable cases.

Confirming a heritable aortic disease diagnosis transforms management into aggressive prevention. For FBN1-related disease, regular imaging (echocardiography or CT/MRI) monitors aortic root diameter; beta-blockers or angiotensin II receptor antagonists slow aortic dilation and delay dissection. Prophylactic aortic root replacement is offered when the aortic root reaches a diameter-specific threshold: typically 5.0-5.5 cm for FBN1, but much smaller (~5.0 cm) for TGFBR1 because dissection risk is higher at smaller diameters. Gene-specific thresholds are critical: using the wrong criterion delays necessary surgery and increases sudden death risk. Identifying a pathogenic variant enables cascade testing of relatives, informing imaging surveillance and surgical planning. Activity restriction (avoiding strenuous sports) is advised.

FBN1, TGFBR1, and MYH11 variants have distinct phenotypes and surgery thresholds: FBN1 typically milder, TGFBR1 more aggressive with lower dissection threshold, MYH11 non-syndromic TAAD.

A vizsgált 4 betegség

• Aortic Aneurysm
• Familial Thoracic Aortic Aneurysm and Dissection
• Multisystemic Smooth Muscle Dysfunction Syndrome
• Familial Thoracic Aortic Aneurysm 11 Susceptibility

Miért a teljes genom szekvenálás

Standard TAAD panels test 11-20 genes but identify mutations in only ~30% of familial non-syndromic thoracic aortic disease.

További cardiovascular conditions

• Arrhythmogenic CardiomyopathyCDH2, DES, DSC2, DSG2
• Brugada SyndromeSCN5A
• Cantú SyndromeABCC9, KCNJ8
• Cardiac-Urogenital SyndromeMYRF
• Catecholaminergic Polymorphic Ventricular TachycardiaCALM1, CALM2, CALM3, CASQ2
• Dilated CardiomyopathyABCC9, ACTC1, BAG3, BAG5
• FLT4-Related Congenital Heart DiseaseFLT4
• Familial Atrial FibrillationGJA5, KCNJ2, KCNQ1, MYL4
• Hereditary Arterial CalcificationABCC6, ENPP1, NT5E
• Hereditary Hemorrhagic TelangiectasiaACVRL1, ENG, GDF2, SMAD4
• Hereditary Vascular MalformationsEPHB4, GLMN, RASA1, TEK
• Heritable Pulmonary Arterial Hypertension (HPAH)ATP13A3, BMPR2, CAV1, EIF2AK4
• Heterotaxy & Laterality DefectsACVR2B, CFAP53, CFC1, CIROP
• Hypertrophic CardiomyopathyACADVL, ACTC1, ALPK3, BRAF
• Inherited Congenital Heart DefectsACTC1, ELN, FLNA, GATA4
• Left Ventricular NoncompactionACTC1, LDB3, MIPEP, MYBPC3
• Loeys-Dietz SyndromeSMAD2, SMAD3, TGFB2, TGFB3
• Long QT SyndromeCACNA1C, CALM1, CALM2, CALM3
• Monogenic Hypertension & Mineralocorticoid DisordersCACNA1D, CACNA1H, CUL3, CYP11B1
• Moyamoya DiseaseACTA2, GUCY1A1, RNF213, SAMHD1
• NR2F2-Related Congenital Anomalies SyndromeNR2F2
• Noonan SyndromeBRAF, CBL, ERF, HRAS
• PLD1-Related Congenital Heart DiseasePLD1
• Primary Lymphoedema & Lymphatic MalformationsADAMTS3, ANGPT2, CCBE1, CELSR1
• Progressive Cardiac Conduction Disease & Sick Sinus SyndromeCACNA1D, DES, HCN4, LMNA
• Restrictive CardiomyopathyTNNI3, TNNT2
• Short Qt SyndromeKCNH2, KCNJ2, KCNQ1, SLC4A3
• Syndromic and Metabolic CardiomyopathiesACTN2, AGK, CAMK2D, NKX2-5
• Tetralogy of FallotKDR, NKX2-5, ZFPM2
• ThrombophiliaF2, F5, F9, HRG