Rare Copy Number Variants Disrupt Genes Regulating Vascular Smooth Muscle Cell Adhesion and Contractility in Sporadic Thoracic Aortic Aneurysms and Dissections

Prakash, Siddharth K.; LeMaire, Scott A.; Guo, Dongchuan; Russell, Ludivine; Regalado, Ellen S.; Golabbakhsh, Hossein; Johnson, Ralph J.; Safi, Hazim J.; Estrera, Anthony L.; Coselli, Joseph S.; Bray, Molly S.; Leal, Suzanne M.; Milewicz, Dianna M.; Belmont, John W.

doi:10.1016/j.ajhg.2013.05.013

Cited by 2 publications

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“…The sample of EM À patients (n ¼ 21) was particularly small, and the absence of any association with GO process terms might be related to low power in this subset of patients. In this group we detected a rare duplication of the MYH11/ABCC6 locus (Supplementary Table 2), which was considered to be disease-related in a study of aortic dissection, 9 as well as a CeAD deletion of the gene encoding SGCZ leading to a frame shift in the coding transcript. It is not unlikely that these CNVs affect the contractility of the smooth muscle cells and predispose to CeAD.…”

Section: Discussionmentioning

confidence: 94%

“…24 A recent study identified various rare CNVs in patients with aortic dissections, disrupting different genetic processes, in particular affecting vascular smooth muscle adhesion and contractility. 9 A large deletion encompassing the COL3A1/COL5A2 locus was identified in another patient with aortic dissection. 25 Our current findings indicate that the genetic disposition to CeAD might be heterogeneous: none of the rare CNVs was found in more than one patient.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8] In patients with sporadic aortic aneurysms and dissections rare CNVs were identified that disrupt genes involved in vascular smooth muscle function. 9 The current study was the first analysis of CNVs in CeAD. The aim of the study was to identify causative genetic deletions and duplications in patients with and without connective tissue alterations.…”

Section: Introductionmentioning

confidence: 97%

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Copy number variation in patients with cervical artery dissection

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Copy number variation in patients with cervical artery dissection

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“…As rare copy nuber variants have recently been associated with susceptibility to TAAD development, 19,20 array-CGH (comparative genome hybridization) analysis was performed in individual VI:1 of family TAAD01 and individual III:4 …”

Section: Genetic Testing and Segregation Analysismentioning

confidence: 99%

Incomplete segregation of MYH11 variants with thoracic aortic aneurysms and dissections and patent ductus arteriosus

et al. 2012

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Thoracic aortic aneurysms and dissections (TAAD) is a serious condition with high morbidity and mortality. It is estimated that 20% of non-syndromic TAAD cases are inherited in an autosomal-dominant pattern with variable expression and reduced penetrance. Mutations in myosin heavy chain 11 (MYH11), one of several identified TAAD genes, were shown to simultaneously cause TAAD and patent ductus arteriosus (PDA). We identified two large Dutch families with TAAD/PDA and detected two different novel heterozygote MYH11 variants in the probands. These variants, a heterozygote missense variant and a heterozygote in-frame deletion, were predicted to have damaging effects on protein structure and function. However, these novel alterations did not segregate with the TAAD/PDA in 3 out of 11 cases in family TAAD01 and in 2 out of 6 cases of family TAAD02. No mutation was detected in other known TAAD genes. Thus, it is expected that within these families other genetic factors contribute to the disease either by themselves or by interacting with the MYH11 variants. Such an oligogenic model for TAAD would explain the variable onset and progression of the disorder and its reduced penetrance in general. We conclude that in familial TAAD/PDA with an MYH11 variant in the index case caution should be exercised upon counseling family members. Specialized surveillance should still be offered to the non-carriers to prevent catastrophic aortic dissections or ruptures. Furthermore, our study underscores that segregation analysis remains very important in clinical genetics. Prediction programs and mutation evaluation algorithms need to be interpreted with caution.

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Rare Copy Number Variants Disrupt Genes Regulating Vascular Smooth Muscle Cell Adhesion and Contractility in Sporadic Thoracic Aortic Aneurysms and Dissections

Cited by 2 publications

References 0 publications

Copy number variation in patients with cervical artery dissection

Copy number variation in patients with cervical artery dissection

Incomplete segregation of MYH11 variants with thoracic aortic aneurysms and dissections and patent ductus arteriosus

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