Gene Validity Classification Summary

Gene/Disease Pair:

BGN : Familial thoracic aortic aneurysm and aortic dissection

HGNC:1044 | OrphaNet: 91387 | OMIM:301870
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
Meester JA et al. 2017 Apr (PMID:27632686); (All following probands associated with syndromic thoracic aortic aneurysm and aortic dissection (TAAD). c.5G>A, p.Trp2* variant in a proband with some segregation evidence. 21 kb del: chrX:152767424-152787984 28 kb del: chrX:152768438-152795976)
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1.5 1.5
Meester JA et al. 2017 Apr (PMID:27632686); (marfanoid skeletal features in sister; aortic root echocardiographic dimensions at the upper limits of normal in the mother. variant: c.908A>C, p.Gln303Pro . Points=1.5 Proband with c.238G>A, p.Gly80Ser wih syndromic TAAD. Points =1.5)
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
Meester JA et al. 2017 Apr (PMID:27632686); (Based on 5 segregations of 21 kb deletion with syndromic form of TAAD. LOD 1.5)
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
Only the proband with isolated TAAD was scored
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2 1.0 1
Heegaard AM et al. 2007 May 29 (PMID:17502576); (Expression: PMID 17502576: BGN localization in the aortas of WT mice was determined by immunohistochemistry and immuno-electron microscopy; BGN detected in all 3 layers of the aortic wall with adventitia the major site of BGN deposition in the mouse. Points 0.5 Biochemical Function: PMID 17502576:Resistance to radial elongation of aortic ring specimens from male bgn-KO and WT mice was compared; The maximum load withstood by KO aortic specimens and their maximum stiffness were significantly lower compared with WT. Points= 0.5)
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1.0 1
Meester JA et al. 2017 Apr (PMID:27632686); (Patient cells: Three alternatively spliced products were observed in cDNA from cultured skin fibroblasts ; major splice products introduce a premature stop codon leading to NMD. )
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 2.0 2
Heegaard AM et al. 2007 May 29 (PMID:17502576); (Biglycan deficiency in male BALB/cA mice has been shown to lead to sudden death due to aortic rupture.)
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) 4

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 4 5.5 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
11/17/2016
EXPERT CURATION (DATE)
LIMITED
12/22/2016
Assertion made by the Aortopathy working group. Strong” for syndromic , X-linked TAAD and “limited” for isolated TAAD. The curation shows strong assertion with syndromic TAAD. There was 1 reported proband with isolated TAAD harboring variant in this gene. Given this, the association with isolated TAAD should be limited.