Gene Validity Curation

WAS - Wiskott-Aldrich syndrome

Gene: WAS (HGNC:12731)
Classification - 10/12/2018
Disease: Wiskott-Aldrich syndrome (MONDO_0010518)
Mode of Inheritance: X-linked inheritance (HP:0001417)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP
Evidence Summary: There is abundant published evidence associating the WAS gene with Wiskott-Aldrich syndrome since the gene-disease relationship was first proposed by Derry et al. (1994). Multiple case level studies have been performed with WAS patients that have variants in the WAS gene. WAS expresses in lymphocytes, spleen and thymus. Northern blot and Western blot analysis for WAS indicated no expression of RNA or protein from B lymphoblasts derived from peripheral blood of WAS patients. Multiple WAS deficient mouse and zebra fish models have been established to show consistent phenotypes with WAS patients, including thrombocytopenia, lymphopenia, defective T cell activation and defects in both the wound-induced inflammatory response and in immune-cell-mediated resistance to bacterial infection. Zebrafish WASp mutant can be rescued by WT hWASp. All of these types of evidence are consistent with a definitive relationship between the WAS gene and Wiskott-Aldrich syndrome.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
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 7 10.5 10
Derry JM et al. 1994 Aug 26 (PMID:8069912); Dobbs AK et al. 2007 Feb (PMID:17250667); Binder V et al. 2006 Oct 26 (PMID:17065640); Andreu N et al. 2003 Oct 18 (PMID:14566484); Sasahara Y et al. 2000 Jan-Feb (PMID:10653325);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 2
1.5
1.5
Derry JM et al. 1994 Aug 26 (PMID:8069912);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 0.5 0.5  
Candidate gene sequencing 2.41 1
Binder V et al. 2006 Oct 26 (PMID:17065640);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 2.41    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 4 2
Derry JM et al. 1994 Aug 26 (PMID:8069912); Binder V et al. 2006 Oct 26 (PMID:17065640); Sasahara Y et al. 2000 Jan-Feb (PMID:10653325);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Snapper SB et al. 1998 Jul (PMID:9697838); Jones RA et al. 2013 Sep 15 (PMID:23868979);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Jones RA et al. 2013 Sep 15 (PMID:23868979);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 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 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
10/12/2018
EXPERT CURATION (DATE)
Definitive
10/12/2018
EVIDENCE SUMMARY
There is abundant published evidence associating the WAS gene with Wiskott-Aldrich syndrome since the gene-disease relationship was first proposed by Derry et al. (1994). Multiple case level studies have been performed with WAS patients that have variants in the WAS gene. WAS expresses in lymphocytes, spleen and thymus. Northern blot and Western blot analysis for WAS indicated no expression of RNA or protein from B lymphoblasts derived from peripheral blood of WAS patients. Multiple WAS deficient mouse and zebra fish models have been established to show consistent phenotypes with WAS patients, including thrombocytopenia, lymphopenia, defective T cell activation and defects in both the wound-induced inflammatory response and in immune-cell-mediated resistance to bacterial infection. Zebrafish WASp mutant can be rescued by WT hWASp. All of these types of evidence are consistent with a definitive relationship between the WAS gene and Wiskott-Aldrich syndrome.