Alternative titles; symbols
ORPHA: 91387; DO: 14004;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.11 | Aortic aneurysm, familial thoracic 4 | 132900 | Autosomal dominant | 3 | MYH11 | 160745 |
A number sign (#) is used with this entry because of evidence that this form of thoracic aortic aneurysm and/or aortic dissection with patent ductus arteriosus mapping to 16p13.13-p12.2 can be caused by mutations in the myosin heavy chain 11 gene (160745).
For a phenotypic description and a discussion of genetic heterogeneity of familial thoracic aortic aneurysm, see 607086.
Glancy et al. (2001) reported 3 generations of a family in which 5 members had aortic dissection and/or patent ductus arteriosus (PDA; 607411). The proband underwent repair of a symptomatic dissecting aortic aneurysm extending from the aortic valve to the innominate artery at age 51. She was later found to have an aortic dissection from the mid-thorax to just above the renal arteries that was treated conservatively, and she died of heart failure at age 67. A daughter of the proband, who had a PDA repaired at age 6, died at age 28 of an extensive dissection of the descending thoracic and abdominal aorta. One son was found to have a small PDA and an aneurysm extending from the aortic sinuses to the diaphragm at age 28, and underwent repair of both but died of left ventricular failure in the early postoperative period. Another son was found to have an aneurysm of the ascending aorta with areas of dissection, and at surgery underwent repair of a PDA and prosthetic replacement of a tricuspid aortic valve and of the ascending aorta. Histologic examination of aortic tissue from the 3 sibs revealed cystic medial necrosis in the first 2 cases and myxomatous degeneration in the latter. A granddaughter, offspring of the deceased son, was found to have PDA at age 7 months, underwent repair at 21 months, and had no evidence of aortic disease 10 years later.
Khau Van Kien et al. (2004) reported a French family composed of 179 members with an abnormally high occurrence of thoracic aortic aneurysm and aortic dissection. Of 40 members in 3 generations investigated, 16 were affected. In addition, 11 cases of patent ductus arteriosus were observed. Segregation analysis of the distribution of these vascular abnormalities was suggestive of a single genetic defect with an autosomal dominant pattern of inheritance. Khau Van Kien et al. (2004) concluded that familial thoracic aortic aneurysm/dissection with PDA may be a distinct mendelian disorder.
Khau Van Kien et al. (2005) performed cine MRI in 42 asymptomatic members and 6 individuals with known aortic aneurysm/PDA from the French family reported by Khau Van Kien et al. (2004). All individuals bearing the disease haplotype, even asymptomatic, displayed a very low level of aortic compliance and distensibility, indicating that aortic stiffness is a subclinical and early manifestation of the disease.
Khau Van Kien et al. (2005) performed a genomewide scan in 40 members from 3 generations of the French pedigree reported by Khau Van Kien et al. (2004). Initial analysis involving only the 7 thoracic aneurysm/dissection cases yielded a maximum lod score of 2.73 at theta = 0.0 on chromosome 16p at marker D16S3068; the lod score increased to 3.56 with inclusion of 5 PDA cases. A maximum lod score of 4.14 near marker D16S3103 was obtained with multipoint linkage analysis; fine mapping delimited a critical 20-cM interval at 16p13.13-p12.2.
One of the genes in the critical linkage region on chromosome 16p identified by Khau Van Kien et al. (2004) is MYH11 (160745), which encodes the smooth muscle myosin heavy chain, a major specific contractile protein produced in the smooth muscle cells. Zhu et al. (2006) reported systematic mutation screening of the MYH11 gene, which showed 2 heterozygous mutations affecting the same allele in the French kindred reported by Khau Van Kien et al. (2004). The first was a substitution of the splice donor site of intron 32 (IVS32+1G-T); the second was a transition in exon 37 resulting in an arg1758-to-gln (R1758Q) amino acid change (160745.0001). Both mutations were identified in all subjects carrying the disease haplotype, but neither was found in 340 normal chromosomes. In the American kindred described by Glancy et al. (2001), they detected a 72-nucleotide deletion within exon 28 of the MYH11 gene (160745.0002).
Pannu et al. (2007) sequenced the MYH11 gene in 3 probands from 3 families with nonsyndromic thoracic aortic aneurysm and dissection (TAAD) in which 1 or more members had patent ductus arteriosus (PDA) and in 93 probands from unrelated TAAD families without PDA, and identified 2 closely linked missense mutations in 1 of the 3 TAAD/PDA families (160745.0003 and 160745.0004) and a different missense mutation in another of the 3 TAAD/PDA families (160745.0005). Histopathologic analysis of aortic sections from a mutation-positive individual from each family revealed smooth muscle cell (SMC) disarray and focal hyperplasia of SMCs in the aortic media, as well as SMC hyperplasia leading to significant lumen narrowing in some of the vessels of the adventitia. Insulin-like growth factor-1 (IGF1; 147440) was upregulated and there was enhanced expression of markers of angiotensin II (106150) vascular inflammation in mutant aortas and explanted SMCs. Pannu et al. (2007) concluded that MYH11 mutations are likely to be specific to the phenotype of TAAD/PDA and to result in a distinct aortic and occlusive vascular pathology, potentially driven by IGF1 and angiotensin II.
Glancy, D. L., Wegmann, M., Dhurandhar, R. W. Aortic dissection and patent ductus arteriosus in three generations. Am. J. Cardiol. 87: 813-815, 2001. Note: Erratum: Am. J. Cardiol. 87: 1438 only, 2001. [PubMed: 11249915] [Full Text: https://doi.org/10.1016/s0002-9149(00)01515-0]
Khau Van Kien, P., Mathieu, F., Zhu, L., Lalande, A., Betard, C., Lathrop, M., Brunotte, F., Wolf, J.-E., Jeunemaitre, X. Mapping of familial thoracic aortic aneurysm/dissection with patent ductus arteriosus to 16p12.2-p13.13 Circulation 112: 200-206, 2005. [PubMed: 15998682] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.104.506345]
Khau Van Kien, P., Wolf, J.-E., Mathieu, F., Zhu, L., Salve, N., Lalande, A., Bonnet, C., Lesca, G., Plauchu, H., Dellinger, A., Nivelon-Chevallier, A., Brunotte, F., Jeunemaitre, X. Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity. Europ. J. Hum. Genet. 12: 173-180, 2004. [PubMed: 14722581] [Full Text: https://doi.org/10.1038/sj.ejhg.5201119]
Pannu, H., Tran-Fadulu, V., Papke, C. L., Scherer, S., Liu, Y., Presley, C., Guo, D., Estrera, A. L., Safi, H. J., Brasier, A. R., Vick, G. W., Marian, A. J., Raman, C. S., Buja, L. M., Milewicz, D. M. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II. Hum. Molec. Genet. 16: 2453-2462, 2007. Note: Erratum: Hum. Molec. Genet. 17: 158 only, 2008. [PubMed: 17666408] [Full Text: https://doi.org/10.1093/hmg/ddm201]
Zhu, L., Vranckx, R., Khau Van Kien, P., Lalande, A., Boisset, N., Mathieu, F., Wegman, M., Glancy, L., Gasc, J.-M., Brunotte, F., Bruneval, P., Wolf, J.-E., Michel, J.-B., Jeunemaitre, X. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nature Genet. 38: 343-349, 2006. [PubMed: 16444274] [Full Text: https://doi.org/10.1038/ng1721]