Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FBN2 : Familial thoracic aortic aneurysm and aortic dissection

HGNC:3604 | OrphaNet: 91387 | OMIM:612570
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 1.0 1
Callewaert BL et al. 2009 Mar (PMID:19006240); Takeda N et al. 2015 Oct (PMID:25975422); Park ES et al. 1998 Jul 24 (PMID:9714438); (19006240 Proband with mild aortic dilation harboring p.Ser1122Pro 25975422 Proband with mild aortic dilation harboring IVS 32 + 5 G>A 9714438 Paediatric aortic root dilatation. Variant IVS31+1G>C Weak evidence . Total points for isolated thoracic aortic aneurysm and aortic dissection (TAAD) =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 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 0
Total Genetic Evidence Points (Maximum 12) 1
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
Carta L et al. 2006 Mar 24 (PMID:16407178); Zhang H et al. 1994 Mar (PMID:8120105); Davis MR et al. 2012 Dec (PMID:22921888); (Biochemical function PMID 16407178: FBN2-/- ;FBN1+/- mice have impaired elastogenesis compared with FBN1-/- alone - implies synergistic roles of FBN1 and 2 in fibre formation. PMID 8120105: immunohistochemistry and ultrastructural analysis localise FBN2 to formation of microfibrils in human and bovine fetal tissue, presence enriched in elastic fibre-rich areas eg aortic media. PMID 22921888: immunohistochemistry to show that FBN2 forms microfibrils. Expression PMID 8120105: expression enriched in elastic fibre-rich areas eg aortic media Protein interaction PMID 16407178: FBN2-/- ;FBN1+/- mice have impaired elastogenesis compared with FBN1-/- alone - implies synergistic roles of FBN1 and 2 in fibre formation.)
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 0.0
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 1.0 1
Carta L et al. 2006 Mar 24 (PMID:16407178); (FBN2-/- ;FBN1+/- mice have impaired elastogenesis compared with FBN1-/- alone - implies synergistic roles of FBN1 and 2 in fibre formation. Double knockouts (FBN1-/-;FBN2-/-) are non-viable just after embryonic day 14.5. )
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
(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 3 4 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
04/17/2016
EXPERT CURATION (DATE)
LIMITED
12/22/2016
Assertion made by the Aortopathy working group. FBN2 is clearly associated with congenital contractural arachnodactyly, however, not with HTAAD. FBN2 could be predictive of thoracic aortic enlargement without evidence of progression to aortic dissection so far