Aortic Valve Disease 1

A number sign (#) is used with this entry because of evidence that aortic valve disease-1 (AOVD1) is caused by heterozygous mutation in the NOTCH1 gene (190198) on chromosome 9q34.

Description

Bicuspid, or bicommissural, aortic valve (BAV) describes an aortic valve with 2 rather than 3 leaflets (Cripe et al., 2004). In 1 to 2% of the population a bicuspid aortic valve is present. Bicuspid aortic valve is frequently an antecedent to aortic valve stenosis or insufficiency. In extreme cases the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome (241550) (Garg et al., 2005). The valve calcification often observed in bicuspid aortic valve is a result of inappropriate activation of osteoblast-specific gene expression. Mutations in the signaling and transcription regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in nonsyndromic autosomal dominant human pedigrees.

Genetic Heterogeneity of Aortic Valve Disease

Also see AOVD2 (614823), caused by mutation in the SMAD6 gene (602931) on chromosome 15q22, and AOVD3 (618496), caused by mutation in the ROBO4 gene (607528) on chromosome 11q24. There is evidence for additional genetic heterogeneity (see MAPPING).

Clinical Features

Over a 30-year period, Roberts and Roberts (1991) studied 186 patients with aortic dissection at autopsy. Fourteen (7.5%) patients showed a bicuspid aortic valve and 2 (1.1%) showed a unicuspid valve. Among the 16 patients with aortic dissection and congenitally malformed valve, the age at death ranged from 17 to 82 years (mean, 52) and 13 (81%) were men. The entrance tear of the aortic dissection was located in the ascending aorta in all 16 patients with a malformed valve but in only 68% of those with a tricuspid aortic valve (which was found in 170 of the 186 patients). The aortic valve was stenotic in 6 of the 16 patients with congenitally malformed valves. Aortic isthmic coarctation was present in 2 of the 16 patients with a malformed valve compared with no patient with a tricuspid aortic valve. Histologic sections of aorta from 10 patients disclosed severe degeneration of the elastic fibers of the media in 9 patients.

McKusick (1972) pointed to the association of congenital bicuspid aortic valve and Erdheim cystic medial necrosis. By echocardiography used for diagnosing bicuspid aortic valve and aortic aneurysm, Pachulski et al. (1991) concluded that aortic dilatation is present in patients with a functionally normal or minimally stenotic bicuspid aortic valve when compared with age- and sex-matched control subjects. These results were confirmed by Hahn et al. (1992), who also used echocardiography to demonstrate a high prevalence of aortic root enlargement in patients with bicuspid aortic valve irrespective of altered hemodynamics or age. The conclusion from this work was that bicuspid aortic valve and aortic root dilation reflect a common developmental defect.

Burks et al. (1998) described 2 young men who developed life-threatening aneurysm or dissection of the ascending aorta. One had a normally functioning bicuspid aortic valve and the other was 10 years after replacement of the aortic valve. The pathology of the aortic media was very similar to that found in Marfan syndrome. Burks et al. (1998) recommended echocardiographic surveillance of the ascending aorta at regular intervals and consideration of beta-adrenergic blockade in patients with significant dilation. The first patient reported by Burks et al. (1998) was an 18-year-old who had had repair of aortic coarctation at the age of 9 years. It was successfully repaired surgically. The second patient was a 36-year-old man who had undergone aortic valve replacement at age 25 because of symptomatic congenital aortic stenosis. The valve was severely deformed, calcified, and bicuspid. The mid-ascending aorta measured 5.9 cm in diameter and was surgically replaced.

Glick and Roberts (1994) could find reports of only 4 families in which more than 1 member had a congenitally bicuspid aortic valve. On the other hand, they had encountered 6 such families with 17 affected members over a period of 27 years. In 3 of the families, a parent and at least 1 child were affected, and in 3 families, 2 or more sibs were affected. In 11 of the 17 family members, the congenital bicuspid nature of the aortic valve was confirmed at the time of aortic valve replacement. In a twelfth patient, the aortic valve was replaced, but the nature of the valve involvement was unknown to Glick and Roberts (1994). In the other 5 patients, the bicuspid aortic valve was demonstrated by echocardiogram in 2 and strongly suggested by aortogram in 3. In the 4 previously reported families, 9 members, all male, were affected; in their group, Glick and Roberts (1994) found 9 males of the 17 affected.

The spectrum of left ventricular outflow tract obstruction (LVOTO) consists of hypoplastic left heart or left ventricle (241550), aortic valve stenosis and bicuspid aortic valve, hypoplastic aortic arch, and coarctation of the aorta (120000). Wessels et al. (2005) described 4 families with presumed autosomal dominant inheritance of LVOTO. In these families, LVOTO showed a wide clinical spectrum, with some members having severe anomalies such as hypoplastic left heart and others having only minor anomalies such as mild aortic valve stenosis. Wessels et al. (2005) concluded that their findings supported the suggestion that all anomalies of the LVOTO spectrum are developmentally related and sometimes can be caused by a single gene defect.

McBride et al. (2005) undertook a formal inheritance analysis of LVOTO in 124 families ascertained by an index case with aortic valve stenosis, coarctation of the aorta, or hypoplastic left heart. LVOTO malformations were noted in 30 relatives, along with significant congenital heart defects in 2 others, yielding a total of 32 (7.7%) of 413 relatives. Relative risk for first-degree relatives in this group was 36.9, with a heritability of 0.71 to 0.90. McBride et al. (2005) concluded that their data supported a complex but most likely oligogenic pattern of inheritance.

Garg et al. (2005) noted that bicuspid and even unicuspid aortic valves typically manifest a ridge where the valve leaflets did not separate in utero.

Patients with NOTCH1 Mutations

Garg et al. (2005) described 2 families with autosomal dominant congenital heart disease with bicuspid aortic valve and calcification. The first family was of European American descent spanning 5 generations with 11 affected individuals. Nine members had aortic valve disease. In 8, an abnormal aortic valve was the only cardiac malformation; 6 had bicuspid aortic valve, and 7 developed calcific aortic stenosis, including 3 cases in the setting of a 3-leaflet valve. One family member had an abnormal mitral valve resulting in mitral stenosis and a ventricular septal defect. Isolated ventricular septal defect or tetralogy of Fallot with bicuspid pulmonary valve was detected in 2 other affected members. The second family was a smaller Hispanic family with aortic valve disease in 3 members in 2 generations. All 3 affected members had bicuspid aortic valve. The proband also had mitral valve atresia, hypoplastic left ventricle, and double-outlet right ventricle; his sib and mother had aortic valve calcification and stenosis.

Loscalzo et al. (2007) performed a prospective study of 13 families with bicuspid aortic valve and thoracic aortic aneurysm (AAT; see 607086). All 13 families had multiple affected members, often in more than 1 generation, consistent with an autosomal dominant pattern of inheritance. Thirty-five percent (39/110) of family members had BAV/AAT or AAT alone. Two families had nonmanifesting obligate carriers, and 3 families had additional left outflow tract anomalies including coarctation of the aorta in 2 families and hypoplastic left heart syndrome in 1 family, suggesting reduced penetrance and variable expressivity. Loscalzo et al. (2007) suggested that BAV and AAT are independent manifestations of a single gene defect.

Mohamed et al. (2006) reported 2 unrelated German patients with BAV and AAT. The first patient was a 49-year-old man with fusion of the left-right and right-coronary aortic valve cusps and a 47-mm diameter ascending aortic aneurysm. In addition, the aortic valve was calcified, with grade I stenosis and insufficiency. The second patient was a 55-year-old man with fusion of the left and right cusps and a 53-mm diameter ascending aortic aneurysm. He also had valve and aortic ring calcification, showing grade I stenosis and insufficiency.

Inheritance

Emanuel et al. (1978) investigated the families of 41 patients with surgically proved isolated bicuspid aortic valves. The minimum frequency of familial occurrence was 17.1%, or 34.1% if doubtful cases were included.

Clementi et al. (1996) reported a family in which 4 members of 2 generations (2 brothers, 1 sister, and her son) had bicuspid aortic valve.

The transmission pattern of AOVD1 in the patients reported by Garg et al. (2005) was consistent with autosomal dominant inheritance.

Population Genetics

Roberts (1970) found a frequency of isolated bicuspid aortic valve of 0.9% in 1,440 autopsies. With the decline in rheumatic fever, congenital bicuspid valve is the most frequent basis of isolated aortic stenosis, being the substrate in over 50% of cases (Roberts, 1970). Some of the pedigrees were consistent with autosomal dominant inheritance with reduced penetrance, particularly in females. A male preponderance has been noted for both bicuspid aortic valve and calcific aortic stenosis. The male preponderance of the latter entity is exaggerated by the superimposition on bicuspid valve of the atherogenic propensity of the male.

Pathogenesis

In 70 patients with bicuspid aortic valve (BAV) and 70 with tricuspid aortic valve (TAV), with or without ascending aortic aneurysm, Balistreri et al. (2018) studied circulating NOTCH1 levels and numbers of endothelial progenitor cells (EPCs). The NOTCH pathway was activated to a greater extent in aneurysmal aortic tissue than in healthy aortic tissue in both BAV and TAV patients. However, BAV patients showed significantly lower levels of tissue and circulating NOTCH pathway components and fewer blood EPCs than TAV patients, regardless of whether aneurysmal disease was present. The authors suggested that deregulation of NOTCH1 and EPCs may be implicated in the development of BAV and the associated vascular complications.

Mapping

In a family of European American descent spanning 5 generations with 11 cases of congenital heart disease, Garg et al. (2005) found linkage of the disorder to a single locus on chromosome 9q34-q35 between D9S1826 and D9qter.

Heterogeneity

Martin et al. (2007) performed a genomewide screen in 353 individuals with bicuspid aortic valve and/or associated cardiovascular malformation from 38 families and obtained a maximum multipoint lod score of 3.8 on chromosome 18q22 at D18S61. The 1-lod unit support interval was between markers D18S68 and D18S1161.

Thanassoulis et al. (2013) performed a genomewide association study (GWAS) of aortic valve calcification among 6,942 participants and mitral annular calcification among 3,795 participants, as detected by CT scanning. One SNP in intron 25 of the LPA gene (152200) on chromosome 6, rs10455872, reached genomewide significance for the presence of aortic valve calcification (OR per allele, 2.05; p = 9.0 x 10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts. Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic valve calcification, supporting a causal role of Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% CI, 1.32 to 2.15) and aortic valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. The combined p value for rs10455872 was 2.8 x 10(-11).

Molecular Genetics

Garg et al. (2005) identified heterozygous NOTCH1 mutations in 2 families with congenital heart disease with bicuspid aortic valve and calcification. One family had a nonsense mutation (R1108X; 190198.0001) and the other family had a single-basepair deletion (190198.0002). Garg et al. (2005) suggested that these families provided insights into the cause of a common human developmental malformation (bicuspid aortic valve) and revealed a potential mechanism mediated by NOTCH1 mutations that may predispose to endothelial dysfunction and inflammation underlying abnormal cardiovascular calcification events.

In a cohort of 48 sporadic German patients with BAV, Mohamed et al. (2006) sequenced the NOTCH1 gene and identified 2 men with BAV and AAT who were heterozygous for missense mutations, T596M (190198.0011) and P1797H (190198.0012), that were not found in public variant databases.

In 48 patients with BAV/AAT, McKellar et al. (2007) performed targeted analysis of NOTCH1 exons previously implicated in familial and sporadic BAV, and observed overrepresentation of NOTCH1 missense variants among the BAV/AAT patients compared to 22 patients who had BAV without AAT, 28 patients with TAV and AAT, and 94 controls with TAV and no AAT.

McBride et al. (2008) analyzed the NOTCH1 gene in 91 unrelated European American patients with congenital aortic valve stenosis, bicuspid aortic valve, coarctation of the aorta (COA; see 120000), and/or hypoplastic left heart syndrome (HLHS; see 241550), and identified heterozygous missense variants in 6 probands. The 2 identified variants were shown to reduce ligand-induced NOTCH1 signaling and were either completely absent or significantly underrepresented in over 200 ethnically matched controls. Four of the mutation-positive probands had aortic valve stenosis and/or bicuspid aortic valve, which in 1 patient was associated with COA, and 2 probands had HLHS. In each case, the NOTCH1 variant was also present in an unaffected parent; McBride et al. (2008) suggested that these variants represent susceptibility alleles that are not sufficient in and of themselves to perturb cardiac development.

Exclusion Studies

In the proband from each of 13 families with bicuspid aortic valve and thoracic aortic aneurysm, Loscalzo et al. (2007) sequenced the TGFBR1 (190181) and TGFBR2 (190182) genes, but found no mutations in either gene.

History

The superior engineering of the tricuspid arterial valve as opposed to either a quadricuspid or a bicuspid valve was recognized by Leonardo da Vinci (McKusick, 1958).

The male preponderance for bicuspid aortic valve is of interest in relation to the fact that this anomaly is frequent in the XO Turner syndrome where it may be the most common cardiac defect; Miller et al. (1983) found that 12 of 35 consecutive patients with Turner syndrome (34%) had isolated, nonstenotic bicuspid aortic valve, as demonstrated by echocardiography. The presence of a systolic ejection click correlated closely with echocardiographic evidence of a bicuspid aortic valve.