Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FBN1 : Familial thoracic aortic aneurysm and aortic dissection

HGNC:3603 | OrphaNet: 91387 | OMIM:134797
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
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 4.5 4.5
Milewicz DM et al. 1996 Dec 1 (PMID:8941093); Katzke S et al. 2002 Sep (PMID:12203992); Francke U et al. 1995 Jun (PMID:7762551); (PMID 8941093: Two novel FBN1 alterations were identified in individuals with Thoracic Aortic Aneurysms (TAAs) involving the ascending thoracic aorta. Dermal fibroblasts from one of the affected individual were used to study the effect of the missense mutation D1155N on fibrillin-1 cellular processing. The mutation decreased the amount of fibrillin-1 deposited into the pericellular matrix. Points 1.5 + 0.5 PMID 12203992: 19 probands with syndromic Aortic dissection/aneurysm/dilation. One with possible isolated TAA with other features not satisfying Ghent nosology for Marfan's syndrome . The others manifest variable degrees of Marfan's. Points 1 PMID 7762551: A Gly1127Ser substitution was present in 9 of 10 affected family members and in 1 young unaffected member but was not found in other unaffected members. Functional studies show reduced FBN deposition in ECM in cultured fibroblasts. 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 4.5 4.5
Francke U et al. 1995 Jun (PMID:7762551); (10 individuals in two generations are affected with abnormalities of the ascending aorta, ranging from mild root dilatation to aortic aneurysm or dissection. See Figure 5 for pedigree. )
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) 9
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2 0.0 0
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 2.0 2
Francke U et al. 1995 Jun (PMID:7762551); Milewicz DM et al. 1996 Dec 1 (PMID:8941093); (PMID 7762551: Functional studies show reduced FBN deposition in extra cellular matrix in cultured fibroblasts from a carrier with Gly1127Ser PMID 8941093 The D1155N mutation decreased the amount of fibrillin-1 deposited into the pericellular matrix)
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 4.0 4
Pereira L et al. 1997 Oct (PMID:9326947); Neptune ER et al. 2003 Mar (PMID:12598898); Judge DP et al. 2004 Jul (PMID:15254584); (PMID: 9326947 Targeted partial deletion of mouse FBN1. Although homozygous mutants did not display skeletal abnormalities , all animals died suddenly of cardiovascular complications. All showed vascular compromise of some sort Including focal fragmentation of elastic fibers, thinning of wall of proximal ascending aorta etc. It did not seem to affect elastic matrix assembly. PMID 12598898 , using the above mice model, observed developmental impairment of distal alveolar septation. By 6 months of age, Fbn1mgR/mgR mice developed marked airspace dilatation associated with destructive changes, peribronchiolar inflammation and greater expression of matrix metalloproteases , recapitulating the pathologic findings of human emphysema. PMID 15254584: Mice heterozygous for a comparable missense mutation (C1039G) revealed impaired microfibrillar deposition, skeletal deformity, and progressive deterioration of aortic wall architecture, comparable to characteristics of the human phenotype. Introduction of a WT FBN1 transgene on a heterozygous C1039G background rescued aortic phenotype. )
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) 6

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 9 6 15 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
Assertion made by the Aortopathy working group.