Mutations in Myosin Light Chain Kinase Cause Familial Aortic Dissections

Wang, Li; Guo, Dongchuan; Cao, Jianjun; Gong, Limin; Kamm, Kristine E.; Regalado, Ellen S.; Li, Li; Shete, Sanjay; He, W.; Zhu, Min; Offermanns, Stefan; Gilchrist, Dawna; Elefteriades, John A.; Milewicz, Dianna M.

doi:10.1016/j.ajhg.2011.03.007

Cited by 78 publications

(107 citation statements)

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“…Because aortic dissection related to variants in MYLK often presents without a history of aortic enlargement, the ACMG StAteMent intervention of echocardiogram may be falsely reassuring and may not prevent sudden cardiac death. 8 In addition, there is insufficient evidence on the appropriate age to begin medications and the efficacy of this intervention to reduce dynamic stress on the aorta. 9 The SFWG considered that additional data on MYLK are likely to be gathered in the coming years from aneurysm genetic testing panels, and this evidence could be reevaluated periodically for possible re-addition of MYLK to the SF list.…”

Section: Resultsmentioning

confidence: 99%

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics

Kalia

Adelman

Bale³

et al. 2017

Genetics in Medicine

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Section: Resultsmentioning

confidence: 99%

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics

Kalia

Adelman

Bale³

et al. 2017

Genetics in Medicine

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1,377

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“…7 Of these nine variants, six are germline variants, and four of these six are reported in association with TAAD (Table 1). 7 Of note, the p.Arg1480Ter and the p.Ser1759Pro variants are listed from the article published by Wang et al 5 Here we report the case of a 25-year old man who died unexpectedly due to an ascending aortic dissection and rupture. Genetic counseling and testing were performed following his death.…”

Section: Introductionmentioning

confidence: 98%

“…In 2010, Wang et al reported two variants in the MYLK gene as likely pathogenic given the predicted damaging effects and the segregation within the families. 5 Although transcribed in all tissues, MYLK is mostly expressed in smooth muscle. 6 MYLK encodes for the myosin light chain kinase (MLCK) enzyme, which plays a crucial role in smooth muscle cell contraction.…”

Section: Introductionmentioning

confidence: 99%

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A Post Mortem Assessment of a 25-Year-Old Man with Ascending Aortic Dissection and a Novel MYLK Variant

et al. 2015

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We report on the process of post mortem evaluation and genetic testing following the death of a 25-year-old man due to ascending aortic dissection leading to aortic rupture. Following the negative clinical testing of a 12-gene thoracic aortic aneurysm and dissection panel, research testing revealed a novel c.5732A>T (p.E1911V) variant in exon 34 of the MYLK gene (NM_053025). Two likely pathogenic variants in this gene have been reported previously in individuals with familial thoracic aortic aneurysm and dissection. Given the unclear clinical consequence of the variant found in our proband, we have classified this change as a variant of uncertain significance. In addition to discussing the complexity involved in variant interpretation, we recognize the need for additional research for more accurate MYLK interpretation. Finally, we comment on the unique challenges of post mortem genetic testing.

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“…MYLK was discovered by a candidate gene sequencing approach. 10 Mutations in SMAD3 were first identified by traditional linkage analysis followed by candidate gene sequencing in patients with syndromic TAAD. 7 Later on SMAD3 mutations were also discovered by whole-exome sequencing in familial non-syndromic TAAD.…”

Section: Introductionmentioning

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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Mutations in Myosin Light Chain Kinase Cause Familial Aortic Dissections

Abstract: In Figure 2B, the label on the right should be NR1-S560dup/NR2B instead of the alternative terminology NR1 (S560_T561InsS)/NR2B.

Cited by 78 publications

References 1 publication

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics

A Post Mortem Assessment of a 25-Year-Old Man with Ascending Aortic Dissection and a Novel MYLK Variant

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

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