ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000016.9) (NC_000016.10)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
16444274 Zhu et al (2006) described two kindreds with thoracic aortic aneurysm and/or aortic dissections (TAAD) and patent ductus arteriosus (PDA). MYH11 was one of several candidate genes sequenced. MYH11 encodes for the smooth muscle myosin heavy chain. The French kindred was found to have two heterozygous mutations in cis: the first was a substitution at the splice-donor site of intron 32 (IVS32+1G>T) and the second was a missense mutation in exon 37 (G5361A) resulting in R1758Q. The IVS32+1G>T mutation on this allele results in an in-frame deletion of 71 amino acids (L1456_N1526del) and thus a deletion of exon 32. In the American kindred in this same study, an in-frame deletion of 72-nucleotides (3810_3881del) in exon 28 leads to the loss of 24 corresponding amino acids (R1241_L1264del). In the French kindred, all individuals with the mutation were found by imaging studies to have marked aortic stiffness, even in clinically asymptomatic. None of these variants was found in 340 normal chromosomes screened. Based on functional studies, the authors postulate a dominant negative mechanism.
21937134 Renard et al (2013) identified a substitution at the same splice-donor site (as described by Zhu et al) , but as a IVS32+1G>A. This variant is also predicted to result in the same in-frame deletion of 71 amino acids, resulting in loss of exon 32. Limited family studies were possible as the proband's affected family members (two sisters and her father) were deceased, but the proband's two unaffected sisters were available and they were negative for this variant.
17666408, 22968129 There have been missense mutations in MYH11 described which seem to have variable expressivity and reduced penetrance (given that some family members with these mutations have no known cardiovascular disease). That was the case for two families with TAAD/PDA described by Pannu et al (2007). One family had two closely linked missense mutations in cis, L1264P (3791T>C) and R1275L (3824G>T) while the other had R712Q (2153C>T). However, mutations in MYH11 seem to be specific to TAAD/PDA as sequencing for MYH11 revealed no mutations in families with TAAD alone. The same reduced penetrance (mutation positive, but unaffected individuals present) and variable expressivity was observed by Harakalova et al (2013) in two Dutch families, each with one of these missense mutations, c.232A>G (p.K78E) in one and 3766-68delAAG in the other. Of interest, the respective mutations only segregated with TAAD/PDA in 3 out of 11 affected family members in the first family and 2 out of 6 affected family members in the second family. And those affected family members had no detectable mutations in other known TAAD genes.

Haploinsufficiency phenotype comments:

All described mutations in MYH11 currently support a dominant-negative model. In addition, MYH11 is part of a recurrent deletion mediated by segmental duplications on 16p13.11 observed in patients with intellectual disability, epilepsy and additional phenotypic features. However, patients with large deletions including this gene have not been reported to have thoracic aortic aneurysm and/or aortic dissections (TAAD) or patent ductus arteriosus (PDA), providing evidence against haploinsufficiency causing this phenotype.

Evidence for gain of function phenotype
PubMed ID Description
21698135 Kuang et al demonstrated that recurrent 16p13.1 duplications involving MYH11 were detected at a statistically significant higher frequency in patients (8/756) with thoracic aortic aneurysms and dissections (TAAD) compared with that of controls (4/4569). Increased MYH11 expression was found in aortic tissues from TAAD patients with 16p13.1 duplications compared with control aortas. MYH11 is the best candidate for the dosage-sensitive gene conferring increased aortic disease risk in patients with 16p13.1 duplication. However, 16p13.1 duplication did not segregate with aortic disease pedigrees with familial TAAD.

Triplosensitivity phenotype comment:

One large-scale case-control study supported the association of 16p13.1 duplication including the MYH11 gene and increased risk for aortic diseases. However, no duplication involving only MYH11 has been reported to be associated with aortic diseases.