Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MYH11 : Familial thoracic aortic aneurysm and aortic dissection

HGNC:7569 | OrphaNet: 91387 | OMIM:160745
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10 0.0 0
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 4.0 4
Pannu H et al. 2007 Oct 15 (PMID:17666408); Renard M et al. 2013 May 10 (PMID:21937134); Harakalova M et al. 2013 May (PMID:22968129); Bee KJ et al. 2012 Dec (PMID:23099432); Takeda N et al. 2015 (PMID:27081537); Zhu L et al. 2006 Mar (PMID:16444274); (PMID 16444274: Systematic mutation screening identified two cis heterozygous mutations affecting in the French kindred IVS32+1GT (splice-donor site of intron 32), p.R1758Q(exon 37) Both mutations were identified in all subjects carrying the disease haplotype, but neither was found in 340 normal chromosomes. Also absent in ExAC. Probands 1 . Points=1 17666408 Variants L1264P and R1275L in coiled coiled domain coseggregated with Thoracic aortic aneurysm and aortic dissection (TAAD) in 3 Generation family. Structural analysis suggested that the mutations found in the TAAD/PDA families are predicted to be deleterious to protein function. Probands 1, Points 0.5 PMID 21937134: In 1 family with TAAD associated with PDA, a causal aberration in MYH11 was found in one family : IVS32+1G mutation in intron 32. This variant was previously reported by PMID 16444274 .ExAC Allele Frequency:0.02% 1 proband, Points=0.5 PMID 22968129: Two different novel heterozygote MYH11 variants were detected in the probands two large Dutch families with TAAD/PDA. However, these variants incomplete segregation with the TAAD/PDA in 3 out of 11 cases in family 1 and in 2 out of 6 cases of family 2. One missense and one inframe deletion was identified. p.K78E was absent in ExAC.No other evidence in support of pathogenicity of variant.However this variant was also identified in a Japanese pedigree (PMID:26056961) segregating TAAD. Number of Probands: 1, Points=0.5 PMID 23099432: MYH11 mutations were identified in three unrelated probands. No other functional tests supporting variant pathogenicity. Number of probands from this study: 1 (p.R1590Q ), Points=0.5 PMID 26056961 : Heterozygous in frame deletion p.K1256del was identified in affected members of two Japanese pedigrees. Cosegregation was shown in one pedigree. One pediatric case with this variant had TAA + PDA but the rest were non syndromic. <0.0001% in ExAC Variant is in a conserved residue of a functional (rod) domain.# of probands from this study : 1 points=0.5 PMID 27081537: Familial case of non-syndromic TAAD with a MYH11 L1264P mutation, in which PDA was not observed. (Authors performed genetic analyses of mutations of the TAAD related genes including FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2, ACTA2 and MYH11) Co-segregation was shown in a 17 member three generation pedigree. This variant was recurrent ( also observed in PMID 17666408) Absent in ExAC. Variant is in a conserved residue of a functional domain. # of probands= 1, Points=1 )
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 0.0 0
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 0.0
Segregation Evidence Evidence of segregation in one or more families LOD Score Examples 3 5 0-7 7 5.0 5
Khau Van Kien P et al. 2005 Jul 12 (PMID:15998682); Pannu H et al. 2007 Oct 15 (PMID:17666408); Renard M et al. 2013 May 10 (PMID:21937134); Bee KJ et al. 2012 Dec (PMID:23099432); (15998682: 3-generation French family with TAAD, patent ductus arteriosus (PDA), or both. Considering only the 7 TAAD cases, max LOD score of 2.73 was obtained at θ=0, at 16p12.2–p13.3 region. If the 5 PDA cases are considered affected, stronger values were observed at this region, with a maximum LOD score of 3. Points 4 17666408: segregation data from family TAA027 was included in the curation. Included but there was PDA in two individuals. Points=1 )
2 4
1.5 3
1 1.5
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12 0.0
Aggregate Variant Analysis 0-6 12 0.0
Total Genetic Evidence Points (Maximum 12) 9
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2 0.5 0.5
Zhu L et al. 2006 Mar (PMID:16444274); (Expression: PMID 16444274: Immunoblotting of proteins extracted from pathological aorta confirmed presence of similar amounts of wild type and mutant SM-MHC. Points 0.5 )
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1.5 1.5
Zhu L et al. 2006 Mar (PMID:16444274); Pannu H et al. 2007 Oct 15 (PMID:17666408); (Patient cells. PMID 16444274: Orcein staining of elastic fibers from probands harboring MYH11 mutations shows decrease in number and rupture of elastic fibers. Actin labelling and alcian staining revealed abnormalities of SMCs and deposition of mucopolysaccharides where SMCs were lost. PMID 17666408 Histopathological analysis of aortic sections from two individuals with MYH11 mutations revealed SMC disarray and focal hyperplasia of SMCs in the aortic media. )
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 1.0 1
Kuang SQ et al. 2012 May 25 (PMID:22511748); Bellini C et al. 2015 Jan 2 (PMID:25433566); (Mild phenotypes PMID 22511748 Myh11 R247C/R247C knock in mice exhibited normal growth, reproduction, and aortic histology but decreased aortic contraction. The decrease in aortic contractility was not associated with aortic pathology in these mice and suggests that decreased aortic contractility alone may not be sufficient to cause thoracic aortic disease. 25433566: The mutant aortas were generally normal , under hypertensive hemodynamics, there was intramural delaminations or premature deaths in 20% of R247C knock-in mice. )
Cell culture model system 1 0 - 2
Rescue in animal model 2 0 - 4
Rescue in engineered equivalent 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 3

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 9 3 12 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
Assertion made by the Aortopathy working group. Association with TAA is strong if patients with Patent Ductus Arteriosus and TAAD are considered together.