Alternative titles; symbols
ORPHA: 91387; DO: 14004; MONDO: 0013418;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q21.1 | Aortic aneurysm, familial thoracic 7 | 613780 | Autosomal dominant | 3 | MYLK | 600922 |
A number sign (#) is used with this entry because of evidence that aortic dissection with or without aortic aneurysm can be caused by heterozygous mutation in the MYLK gene (600922) on chromosome 3q21.
For a general phenotypic description and discussion of genetic heterogeneity of thoracic aortic aneurysm, see AAT1 (607086).
Wang et al. (2010) studied affected individuals from 2 unrelated families with thoracic aortic dissection (families TAA026 and TAA400) and mutations in the MYLK gene. Acute aortic dissections occurred with little to no aortic enlargement in these patients. Examination of ascending aortic tissue from 2 affected members of family TAA026 indicated medial degeneration of the aorta, characterized by increased proteoglycan deposition and mild elastic fiber thinning and fragmentation, along with a significant increase in the presence of small arteries in the medial layer of the aorta. Wang et al. (2010) noted that a similar increase of arteries in the medial layer had been described in patients with mutations in the MYH11 gene (160745) (see Pannu et al. (2007) and AAT4, 132900).
Hannuksela et al. (2016) reported a large Swedish family in which 5 individuals over 3 generations had aortic dissection. Three patients died from thoracic aortic dissection or rupture, whereas 2 survived an acute type A thoracic aortic dissection. An additional family member had intramural hematoma of the descending aorta. Histologic analysis of aortic specimens from 3 patients with dissection or rupture showed discontinuities in elastin fibers in the medial layer and surrounding the ruptured area. No pathologic findings were visible in the smooth muscle cells, and there was no significant increase of arteries in the medial layer. Phenotypic variability was evident in the family, with dissections occurring between 23 years and 77 years of age. At the time of dissection, ascending aorta diameter varied from near-normal to dilated.
Shalata et al. (2018) studied a large consanguineous Arab family in which 9 individuals had thoracic aortic aneurysm and dissection. The authors noted that the patients could be divided clinically into 2 groups: 6 of the patients presented at an earlier age, with average age at onset of 35 years, and had more severe disease with an almost uniformly fatal outcome (5 deaths). These patients exhibited extensive arterial dissections involving many arteries, including the renal, iliac, superior mesenteric, subclavian, and innominate arteries. All had aortic dissections; however, none had unequivocal evidence of aortic aneurysm at the time of dissection. The remaining 3 patients presented in the sixth or seventh decade of life, and 2 of them had only aortic involvement; the third patient, who was deceased, also showed involvement of the renal, iliac, and superior mesenteric arteries. Cystic medial necrosis was seen in all aortic samples from patients who underwent endovascular repair.
Wang et al. (2010) analyzed the MYLK gene in 193 probands from unrelated families in which 2 or more members had thoracic aortic aneurysms or dissections. They identified 2 heterozygous variants (600922.0001 and 600922.0002) that segregated with aortic dissections in 2 families (TAA026 and TAA400, respectively), and were not found in 188 ethnically matched controls. Three additional MYLK variants were identified in 3 unrelated probands that were not detected in controls, but family members were not available for segregation analysis. Incomplete penetrance was observed in 1 of the families (TAA400), in which 5 asymptomatic individuals with ages ranging from 59 years to 76 years carried the same MYLK mutation as the affected father and son. The authors stated that familial aortic disease is typically inherited in an autosomal dominant fashion with decreased penetrance and variable expression.
In a large Swedish family segregating autosomal dominant aortic dissection, Hannuksela et al. (2016) performed exome sequencing and identified a 2-bp deletion in the MYLK gene causing a premature termination codon (S1091X) that was present in all 5 affected individuals as well as 9 unaffected family members. In addition, a family member with an intramural hematoma of the descending aorta did not carry the mutation. There were no differences in aortic diameter or stiffness between mutation carriers and noncarriers.
Luyckx et al. (2017) screened a cohort of 358 cases of aortic aneurysmal disease for mutations in thoracic aortic aneurysm-associated genes and identified 2 probands with hypertension and type B aortic dissections in the fifth decade of life who were heterozygous for nonsense mutations in the MYLK gene (Q1458X and R1487X). In the first family, the Q1458X mutation was also identified in the patient's unaffected father, and in the second family, the R1487X mutation was also present in the proband's unaffected half brother.
In a large consanguineous Arab family with thoracic aortic aneurysm and dissection, Shalata et al. (2018) identified a missense mutation in the MYLK gene (A1491S; 600922.0005) that was not found in 100 ethnically matched controls or public variant databases. The mutation was present in homozygosity in 6 severely affected family members with early-onset disease, 5 of whom were deceased, and was found in heterozygosity in 3 individuals with a later age of onset, 1 of whom was deceased; the mutation was also present in heterozygosity in 16 asymptomatic family members. The authors stated that the most appropriate designation for mode of inheritance in this family was autosomal dominant with incomplete penetrance.
Hannuksela, M., Stattin, E.-L., Klar, J., Ameur, A., Johansson, B., Sorensen, K., Carlberg, B. A novel variant in MYLK causes thoracic aortic dissections: genotypic and phenotypic description. BMC Med. Genet. 17: 61, 2016. Note: Electronic Article. [PubMed: 27586135] [Full Text: https://doi.org/10.1186/s12881-016-0326-y]
Luyckx, I., Proost, D., Hendriks, J. M. H., Saenen, J., Van Craenenbroeck, E. M., Vermeulen, T., Peeters, N., Wuyts, W., Rodrigus, I., Verstraeten, A., Van Laer, L., Loeys, B. L. Two novel MYLK nonsense mutations causing thoracic aortic aneurysms/dissections in patients without apparent family history. Clin. Genet. 92: 444-446, 2017. Note: Erratum: Clin. Genet. 93: 938 only, 2018. [PubMed: 28401540] [Full Text: https://doi.org/10.1111/cge.13000]
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]
Shalata, A., Mahroom, M., Milewicz, D. M., Limin, G., Kassum, F., Badarna, K., Tarabeih, N., Assy, N., Fell, R., Cohen, H., Nashashibi, M., Livoff, A., Azab, M., Habib, G., Geiger, D., Weissbrod, O., Nseir, W. Fatal thoracic aortic aneurysm and dissection in a large family with a novel MYLK gene mutation: delineation of the clinical phenotype. Orphanet J. Rare Dis. 13: 41, 2018. Note: Electronic Article. [PubMed: 29544503] [Full Text: https://doi.org/10.1186/s13023-018-0769-7]
Wang, L., Guo, D., Cao, J., Gong, L., Kamm, K. E., Regalado, E., Li, L., Shete, S., He, W.-Q., Zhu, M.-S., Offermanns, S., Gilchrist, D., Elefteriades, J., Stull, J. T., Milewicz, D. M. Mutations in myosin light chain kinase cause familial aortic dissections. Am. J. Hum. Genet. 87: 701-707, 2010. Note: Erratum: Am. J. Hum. Genet. 88: 516 only, 2011. [PubMed: 21055718] [Full Text: https://doi.org/10.1016/j.ajhg.2010.10.006]