Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FOXE3 : Familial thoracic aortic aneurysm and aortic dissection

HGNC:3808 | OrphaNet: 91387 | OMIM:601094
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
Kuang SQ et al. 2016 Mar 1 (PMID:26854927); (FOXE3 c.457G>C (p.Asp153His), segregated with aortic disease in TAA337. This variant is present once in 13,000 chromosomes in the ESP database and disrupts an evolutionarily conserved amino acid. Proband from this family is considered. Exome and Sanger sequencing of 564 unrelated FTAAD probands identified 7 additional FOXE3 rare variants predicted to disrupt the protein: p.Pro112Ser, p.Gly137Asp, p.Asp156Asn, p.Arg164Ser, p.Gly196Ala, p.Pro202Leu, and p.Ser300Gly. Variant p.Gly137Asp was identified in affected members of a small family with aortic root dilatation ; no additional samples were available from the other families. Thus considering only these two probands with a total point of 2.)
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 5.0 5
Kuang SQ et al. 2016 Mar 1 (PMID:26854927); (FOXE3 c.457G>C (p.Asp153His), segregated with aortic disease in TAA337 . Segregation of the FOXE3 variant with aortic disease in this family revealed a lod score of 3.00. )
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) 7
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
Kuang SQ et al. 2016 Mar 1 (PMID:26854927); (Expression: Foxe3 expression induced in aortas of WT mice stressed with TAC 1 points.)
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 5.0 4
Kuang SQ et al. 2016 Mar 1 (PMID:26854927); (Model System: 1) Morpholino knock-down in Zebrafish resulting in Disrupted aortic arches. Clear effect on aortic development; direct parallel with aortic dissection unclear. 2) Rescue in engineered equivalent; Significant rescue of phenotype with wild-type copy; only partial rescue with patient variant.Not technically a cellular phenotype, but clearly phenotype in model organism which is relevant to disease - perhaps strong enough to note but not earning "maximum" points for rescue. 3) Mouse KO model with reduced smooth muscle cell number and density; on further stressing with transverse aortic constriction (TAC), evidence of aortic rupture, intramural haematoma. Model shows clear parallel phenotype - but also suggests knockout may not by itself be sufficient for phenotype. 4 points for model system, 1 point for rescue.)
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 7 5 12 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)
STRONG
03/09/2016
EXPERT CURATION (DATE)
MODERATE
06/15/2016
Assertion made by the Aortopathy working group. Recent gene, no strong replication of the data so far. Additional data to confirm clinically relevant HTAAD required - 1 point subtracted