Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

LOX : Familial thoracic aortic aneurysm and aortic dissection

HGNC:6664 | OrphaNet: 91387 | OMIM:153455
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 3.0 3
Guo DC et al. 2016 Mar 18 (PMID:26838787); (Two nonsense mutations early in the protein W42* and G202*. Points=3)
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 3.0 3
Guo DC et al. 2016 Mar 18 (PMID:26838787); Lee VS et al. 2016 Aug 2 (PMID:27432961); (PMID 26838787: WES in one family with thoracic aortic aneurysm and aortic dissection (TAAD) identified a rare coding variant in LOX; exome and/or Sanger sequencing of LOX performed in an additional 410 probands from unrelated families. 8 rare coding variants identified - 6 probands with variants predicted to be damaging to protein (4 missense mutations were considered to be affecting the final protein) . Points=3 *0.5+ 1 PMID 27432961: WES in two first cousins with TAAD identified a rare missense mutation in LOX that co-segregated with disease in a family with a two-generational history of aortic dissection. Points=.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 3.0 3
Guo DC et al. 2016 Mar 18 (PMID:26838787); Lee VS et al. 2016 Aug 2 (PMID:27432961); (PMIDs 26838787 and 27432961: Only family with p.Ser280Arg considered for segregation evidence( TAA602). Inferred LOD score from 6 segregations (combined families). Point= 3 )
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 1.0 1
Guo DC et al. 2016 Mar 18 (PMID:26838787); Wakasaki H et al. 1990 Sep (PMID:1975633); Lee VS et al. 2016 Aug 2 (PMID:27432961); (Biochemical Function: PMID 26838787: Aortas from two patients with LOX variants, Ser280Arg and Gly202*, showed mild medial degeneration characterized by focal loss of elastin fibers and smooth muscle cells (SMCs) but limited deposition of proteoglycans. PMID 27432961: Histopathological analysis of resected aortic tissue (II-1) showed cystic medial necrosis with a disorganized appearance of collagen and elastic lamellae. Expression: PMID 1975633: Localization of lysyl oxidase investigated in various tissues and cultured cells using an immunofluorescent antibody method; monoclonal antibodies showed strong immunostaining in the aorta and dermal connective tissue suggesting a close relation to elastin and collagen. )
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1.0 1
Guo DC et al. 2016 Mar 18 (PMID:26838787); Lee VS et al. 2016 Aug 2 (PMID:27432961); (Non-patient cells PMID 26838787: Mutant LOX constructs expressed in Hela cells assayed for lysyl oxidase activity; Thr248Ile, Ser280Arg, and Ser348Arg had lysyl oxidase activity levels that were 92%, 50%, and 79% of that of WT LOX, respectively. PMID 27432961:Lox activity in MEFs cultured from WT animals significantly higher than that from homozygous mutant knock-in animals. )
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 4.0 4
Mäki JM et al. 2002 Nov 5 (PMID:12417550); Mäki JM et al. 2002 Nov 5 (PMID:12417550); Hornstra IK et al. 2003 Apr 18 (PMID:12473682); (PMID 12417550: Cre-Lox mediated targeted deletion of first exon; mixed 129/SvJ × C57BL/6 background LOX(−/−) mice died at the end of gestation or as neonates; necropsy of the live-born pups revealed large aortic aneurysms Microscopic analysis of the aorta demonstrated highly fragmented elastic fibers and discontinuity in the smooth muscle cell layers PMID 12473682: LoxP mediated disruption of first exon; mixed 129/SvJ × C57BL/6 background LOX(−/−) mice died soon after parturition, exhibiting cardiovascular instability with ruptured arterial aneurysms and diaphragmatic rupture. Microscopic analysis of the aorta demonstrated fragmented elastic fiber architecture )
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
(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 9 6 15 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
05/13/2016
EXPERT CURATION (DATE)
STRONG
07/25/2016
Assertion made by the Aortopathy working group.