Bicuspid aortic valve (BAV; OMIM #109730, ORPHA:402075) is the most common congenital heart disease with an estimated prevalence of 0.5–0.8% [81]. Although BAV can be part of the phenotype in some cases of sHTAD such as MFS or LDS [82], there is also mounting evidence of familial clustering in up to 6–9% of first-degree relatives of nonsyndromic BAV [83,84]. An autosomal dominant inheritance pattern with variable expressivity and typically incomplete penetrance is recognized [82,84]. Up to 75% of patients with BAV might develop aortic dilatation [85], although this typically occurs later than other syndromic or nonsyndromic HTAD and at relatively slower growth rates (average of 0.19 cm/year) [86].

Variants in the NOTCH1 gene have been described in approximately 1% of sporadic BAV cases and in up to 7% of familial BAV cases [82,87,88] and are typically associated with prominent valve calcification [89]. Recently, loss-of-function SMAD6 variants have been found in up to 11% of nsHTAD patients with BAV [90,91]. ROBO4 variants, encoding a factor known to contribute to endothelial performance, and TBX20 variants, a transcription factor involved in the regulation of heart development, were shown to contribute to aortic aneurysm formation in families with nonsyndromic BAV [92,93].

Echocardiography screening of first-degree relatives of patients with BAV should be offered especially in boys, athletes and if hypertension is present [24]. Families with multiple affected relatives, a combination of other left-sided congenital abnormalities and a particularly malignant clinical profile should be offered genetic testing for at least ACTA2, SMAD6, TBX20, ROBO4 and NOTCH1 genes. Multiple gene panels should be considered in selected cases, taking into consideration the variable and incomplete penetrance of sHTAD that might lead to a mild phenotype with minimal or no systemic features in some patients. No specific genotype–phenotype correlations currently exist that could possibly guide surgical interventions or provide specific prognostic information. Recently, Pileggi et al. indicated that specific NOTCH1 variants could be associated with better prognosis and later-onset development of aortic stenosis [88].

Based on the presence of familial disease or not, nsHTAD is further categorized into familial and sporadic nsHTAD. A positive family history of thoracic aortic disease is associated with an increased aortic growth rate, a bigger chance of gene identification and earlier phenotypic manifestation [94]. The genetic etiology of familial nsHTAD is highly heterogeneous and usually involves genes that regulate the smooth muscle cell contractile apparatus. The genetic substrate of sporadic nsHTAD is largely unknown and seems to differ from familial nsHTAD cases.

To date, over 10 genes and 2 linked loci have been involved in the pathogenesis of nsHTAD, including genes involved in the (TGF-β) pathway and genes encoding extracellular matrix proteins that are typically associated with syndromic aortopathies [2,6,47]. Common single nucleotide polymorphisms at the 15q21.1 locus of the FBN1 gene have been shown to be associated with sporadic nsHTAD [95] without other systemic features of MFS. Arnaud et al. performed genetic screening in 226 consecutive nsHTAD, either sporadic in patients under 45 years of age or in documented familial cases, and identified an overall yield of pathogenic or likely pathogenic variants (SMAD3, FBN1, TGFBR1, TGFBR2, TGFB2, ACTA2, MYLK, FLNA, FBN2, LOX, MFAP5 genes) in 18% of the patients (11% in sporadic cases vs. 22% in familial cases), with almost two-thirds located in SMAD3 and FBN1 genes. Exclusively missense variants and no premature termination codon variants were identified in the FBN1 gene in this cohort. More careful clinical evaluation after the genetic result revealed clinical findings consistent with LDS in approximately half of the cases with SMAD3 variants and history of periventricular heterotopia in patients with the FLNA variant, reclassifying these cases as syndromic [6]. Weerakkody et al. investigated a cohort of 1025 unrelated HTAD cases, including many cases of sporadic HTAD, and reported a 4.9% yield of genetic testing for a 15-gene genetic panel. Patients with a family history of HTAD were four times more likely to carry a pathogenic or likely pathogenic variant than those without a family history (9.8 vs. 2.4%) [96]. Since clinical information (syndromic features or clinical diagnosis) was not available in a significant percentage of the cases, these cases cannot automatically be categorized as sporadic nsHTAD.

Overall, pathogenic ACTA2 variants are the most frequently encountered, as they are detected in 1–21% of nsHTAD [57,97,98] and are associated with a malignant aortic phenotype. Pathogenic variants in the MYLK gene [99,100,101], with missense pathogenic variants showing an earlier onset aortic event, and variants in the MYH11 [102] and PRKG1 genes [103] have also been recognized as relatively rare but aggressive causes of thoracic aortic dissection (~1% prevalence of each), in nsHTAD which are not always preceded by obvious aortic dilatation. There is no evidence to date that defects in the other genes identified (LOX, MFAP5, FOXE3, MAT2A, SMAD2, SMAD4, NOTCH1, PLOD1, TGFB2, TGFBR2, FBN1, FBN2) are linked to a more severe phenotype or earlier presentation of HTAD [6,57,58].