Gene Validity Curation

Gene Validity Classification Summary

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
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
0.0
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 )
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.)
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) 6
Experimental Evidence
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.)
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. )
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 )
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)*
CALCULATED CLASSIFICATION (DATE)
MODERATE
04/06/2016
EXPERT CURATION (DATE)
STRONG
12/18/2016
Assertion made by the Aortopathy working group. Experts added 1 point, originally moderate classification.