| Gene/Disease Pair: | MYLK : Familial thoracic aortic aneurysm and aortic dissection |
| HGNC:7590 | OrphaNet: 91387 | OMIM:600922 | |
| Mode of Inheritance: | Autosomal dominant inheritance (HP:0000006) |
Genetic Evidence
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Case-Level Data
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Evidence Type | Case Information Type | Guidelines | Scores | PMIDs/Notes | ||||||
| Default | Range | Max | Points | Tally | ||||||||
Variant Evidence
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Autosomal Dominant or X-linked Disorder | Variant is de novo | 2 | 0-3 | 12 |
0.0
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0 | |||||
| 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 | 2.0 | 2 |
Wang L et al. 2010 Nov 12 (PMID:21055718); Ziganshin BA et al. 2015 Nov (PMID:26188975); Proost D et al. 2015 Aug (PMID:25907466); (PMID 21055718: Panel sequencing of a few candidate genes in 94 probands from families with thoracic aortic aneurysm and aortic dissection (TAAD). 1 variant in MYLK absent in ethnically matched controls (+ 4 others) p.S1759P. Also identified a p.R1480X in an unrelated proband. Additional 3 variants in 3 other probands: p.A1754T, p.V1213M p.E1399K not present in ethnically-matched controls but no family data . Points =1 due to lack of gene impact evidence (ignored the latter three missense variants).
PMID 26188975: Found a mutation (p.P1759S) reported earlier in 1 proband; segregated with disease in her family. Points= 0.5
PMID 25907466: Identified one proband with p.R1487* . Points=0.5
)
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| 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 | 4.0 | 4 |
Wang L et al. 2010 Nov 12 (PMID:21055718); Ziganshin BA et al. 2015 Nov (PMID:26188975); (PMID 21055718: Panel sequencing of a few candidate genes in 94 probands from families with TAAD
1 variant in MYLK absent in ethnically matched controls (+ 4 others) p.S1759P segregated with disease in family (3 probands).
Further sequencing of MYLK in 99 probands with additional TAAD – found another variant
(p.R1480X) that segregated with disease in family LOD score 1.2 (increased to 1.8 with addition of family members who had sudden death) Points 3
PMID 26188975: weak segregation data. Less than 4 convincing segregations. 1 point.)
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| 2 | 4 | |||||||||||
| 1.5 | 3 | |||||||||||
| 1 | 1.5 | |||||||||||
Case-Control Data
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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) | 6 | |||||||||||
Experimental Evidence
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Evidence Category | Evidence Type | Guidelines | Scores | PMIDs/Notes | |||||||
| Default | Range | Max | Points | Tally | ||||||||
| Function | Biochemical Function | 0.5 | 0 - 2 | 2 | 2.0 | 2 |
Gao N et al. 2013 Mar 15 (PMID:23362260); Basu S et al. 2013 Apr 19 (PMID:23482558); Basu S et al. 2016 Feb 5 (PMID:26703474); (PMID 23362260: A 50% decrease in MLCK (=MYLK) in aortic smooth muscle resulted in 40% inhibition of myosin regulatory light chain phosphorylation and aorta contractile responses, whereas a 90% decrease profoundly inhibited both responses.
PMID 23482558: Demonstrated that NOTCH1 induced MYLK expression. Knocked out NOTCH1 signaling in vascular smooth muscle cells (vSMC) in mice. This reduced MYLK expression and activity. Supported by report of NOTCH1-responsive element in MYLK promoter
PMID 26703474 showed co-immunoprecipitation of MYLK promoter and JAGGED1 ligand & also MYLK promoter with NOTCH1-enhanced myocardin/SRF complex, & demonstrated each of these enhanced MYLK expression.) |
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| Protein Interaction | 0.5 | 0 - 2 | ||||||||||
| Expression | 0.5 | 0 - 2 | ||||||||||
| Functional Alteration | Patient cells | 1 | 0 - 2 | 2 | 1.0 | 1 |
Wang L et al. 2010 Nov 12 (PMID:21055718); (Patient cells:
Authors transfected COS7 cells with mutations p.S1759P and p.A1754T. Demonstrated significantly reduced (p.1754T) ) or abolished (p.S1759P) calmodulin binding in transfected cells & reduced kinase activity.
)
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| Non-patient cells | 0.5 | 0 - 1 | ||||||||||
| Models & Rescue | Animal model | 2 | 0 - 4 | 4 | 2.0 | 2 |
Wang L et al. 2010 Nov 12 (PMID:21055718); (Authors generated a tamoxifen-induced, SMC specific knockout of MYLK & examined aortas after 13 days.
Increased proteoglycan deposition in aortic media
Increased collagen deposition in adventitia
Increased expression of MMP2
No aortic phenotype (mice with SMC – specific k/o usually die due to low BP, reduced gut mobility, airway constriction and urinary dysfunction) - note low BP similar to ACTA2 k/o effects
) |
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| 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) | 5 | |||||||||||
| Assertion criteria | Genetic Evidence (0-12 points) | Experimental Evidence (0-6 points) |
Total Points (0-18) |
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 Evidence |
> 2 pubs w/ convincing evidence over time (>3 yrs) | ||
| Assigned Points | 6 | 5 | 11 | YES | ||
| CALCULATED CLASSIFICATION | LIMITED | 1-6 | ||||
| MODERATE | 7-11 | |||||
| STRONG | 12-18 | |||||
| DEFINITIVE | 12-18 AND replication over time | |||||
| Valid contradictory evidence (Y/N)* |
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| CALCULATED CLASSIFICATION (DATE) |
MODERATE
04/06/2016
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| EXPERT CURATION (DATE) |
STRONG
12/18/2016
Assertion made by the Aortopathy working group.
Experts added 1 point, originally moderate classification.
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