Gene Validity Classification Summary

Gene/Disease Pair:

NOTCH1 : Familial thoracic aortic aneurysm and aortic dissection

HGNC:7881 | OrphaNet: 91387 | OMIM:190198
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 1.0 1
Kerstjens-Frederikse WS et al. 2016 Sep (PMID:26820064); (A cohort of 427 patients (286 male, 141 female) with non-syndromic LVOTO 147 of 427 probands (34%) the heart defect was familial. 13 novel pathogenic NOTCH1 mutations in 427 index patients (probands) (3%): eight truncating (nonsense or frameshift) mutations, four RNA splicing mutations and one whole gene. Deletion. Their phenotypes included not only LVOTO, but also conotruncal malformations and thoracic aortic aneurysms (TAA) p.(Arg1984*): 1 proband. Aortic valve defects + TAA p.(Ser2486Leufs*21): 1 proband . TAA+ Aortic valve defects (NOTE: the mutation is in last Exon. ) otal points given is 1 as no isolated TAA was observed. )
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 0.5 0.5
Mohamed SA et al. 2006 Jul 14 (PMID:16729972); (Analysis of NOTCH1 mutation frequency and spectrum in 48 patients with sporadic BAV. 12 patients had Aneurysm of ascending aorta. Potential relevant pathogenic mutations identified p.P1797H: Absent in ExAC. Pt with this mutation: aortic valve calcified and insufficient + ascending aortic aneurysm. 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 0.0 0
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) 1.5
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
Garg V et al. 2005 Sep 8 (PMID:16025100); (Expression: Activation of Notch signaling is increased in the aortic wall of DTAAD patients )
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1.0 1
Kostina AS et al. 2016 Apr (PMID:26876948); (Patient cells: Notch-dependent endothelial-to-mesenchymal transition is attenuated in patients with aortic aneurysm and bicuspid aortic valve )
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 0.0
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) 1.5

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 1.5 1.5 3 NO
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)
LIMITED
03/27/2016
EXPERT CURATION (DATE)
LIMITED
04/06/2016
Assertion made by the Aortopathy working group. Association with BAV is strong but not isolated HTAAD.NOTCH1 may be predictive of thoracic aortic enlargement without evidence of progression to aortic dissection so far