Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

EFEMP2 : Familial thoracic aortic aneurysm and aortic dissection

HGNC:3219 | OrphaNet: 91387 | OMIM:604633
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)

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 0.0 0
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 3
Al-Hassnan ZN et al. 2012 Jun 1 (PMID:22440127); (9 patients, from 4 unrelated consanguineous families, with recessively inherited AA. Echocardiogram revealed a wide spectrum of severity of the AA, with a Z-score varying from 5 to 33. In 1 family, genome-wide single-nucleotide polymorphism analysis detected a homozygous block, shared by 2 affected siblings, on chromosome 11 at q13. Sequence analysis of EFEMP2 , located on chromosome 11 at q13, identified a novel homozygous mutation (p.E161K) in all 9 affected subjects. Clinical features reported not complete (e.g no explanation for cyanosis as presenting feature reported - lung- peripheral artery- and pulmonary artery involvement unclear. )
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3.0
Segregation Evidence Evidence of segregation in one or more families LOD Score Examples 3 5 0-7 7 0.0 0
Al-Hassnan ZN et al. 2012 Jun 1 (PMID:22440127); (Combined family segregations to estimate. Points 3*1)
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) 3
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
Huawei P et al. 2014 Feb (PMID:23518852); Horiguchi M et al. 2009 Nov 10 (PMID:19855011); (Expression: PMID 23518852: in aortic wall of ascending aortic dissection from 10 patients , the expression of fibulin-4 protein was significantly reduced. Protein interaction PMID 19855011: In vitro N-terminal domain of FBLN4 interacts with the propeptide domain of LOX. Also immunostaining of cultured human skin fibroblasts revealed colocalization of LOX +FBLN4. )
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1.0 1
Papke CL et al. 2015 Oct 15 (PMID:26220971); (Non patient cells: Fibulin-4 is important for the integrity of aortic collagen in addition to elastin. Smooth muscle-specific Efemp2 loss in mouse (SMKO) resulted in altered fibrillar collagen localization with larger, poorly organized fibrils. LOX activity was decreased in Efemp2-null cells, and collagen cross-linking was diminished in SMKO aortas. )
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 4.0 4
McLaughlin PJ et al. 2006 Mar (PMID:16478991); Hanada K et al. 2007 Mar 16 (PMID:17293478); Horiguchi M et al. 2009 Nov 10 (PMID:19855011); Huang J et al. 2010 Feb 19 (PMID:20019329); Igoucheva O et al. 2015 Aug 28 (PMID:26178373); (PMID 16478991 fibulin-4 knock out (KO) mice exhibited severe lung and vascular defects including emphysema, artery tortuosity, irregularity, aneurysm, rupture, and resulting hemorrhages. PMID 17293478: Fibulin-4 knockdown mice with a hypomorphic expression allele. Mice homozygous for the Fibulin-4 reduced expression allele show dilatation of the ascending aorta and a tortuous and stiffened aorta, resulting from disorganized elastic fiber networks. PMID: 19855011(conditional KO), 20019329 (tissue specific KO), 26178373(variant E57K Knock-in) All result in aneurysmal dialation/dissection of aorta. )
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 3 6 9 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
Assertion made by the Aortopathy working group. Definitive association with cutis laxa phenotype, association with HTAAD less well established - no mutations identified in large cohorts of patients presenting with HTAAD. EFEMP2 may be predictive of thoracic aortic enlargement without evidence of progression to aortic dissection so far