Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CYLD : Brooke-Spiegler syndrome

HGNC:2584 | MONDO_0011512
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hereditary Cancer
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

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 11 10
Bignell GR et al. 2000 Jun (PMID:10835629); Nasti S et al. 2009 Nov (PMID:19807742);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 2
1
1
Hu G et al. 2003 Oct (PMID:14632188); Almeida S et al. 2008 Mar (PMID:17851586);
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 1 1  
Candidate gene sequencing 3.61 1
Hu G et al. 2003 Oct (PMID:14632188);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.61    
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 1
0.5
2
Brummelkamp TR et al. 2003 Aug 14 (PMID:12917690);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 3 1.5
Zuo YG et al. 2007 Oct (PMID:17662085); Massoumi R et al. 2006 May (PMID:16484982);
Functional Alteration Patient cells 1 0 - 2 2 1
1
2
Tauriello DV et al. 2010 Mar 12 (PMID:20227366);
Non-patient cells 0.5 0 - 1 1 1
Massoumi R et al. 2006 May 19 (PMID:16713561);
Models Non-human model organism 2 0 - 4 4 1 2 2
Massoumi R et al. 2006 May 19 (PMID:16713561);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
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
12/21/2018
EXPERT CURATION (DATE)
Definitive
12/21/2018
EVIDENCE SUMMARY
There is abundant evidence published associating the CYLD gene with Brooke-Spiegler syndrome, since the gene-disease relationship was first proposed by Bignell et al. (2000). Multiple case level studies have been performed with BSS patients that have variants in the CYLD gene. CYLD protein is prominently expressed in the inner root sheath of hair follicles of human scalp as well as in eccrine glands. Multiple articles reported no CYLD protein expression in the tumour tissue from BSS patients. Loss of CYLD inhibits apoptosis by activating NF-kappaB. Cyld also negatively regulate cell proliferation in keratinocytes and human Cylindroma tumors display hyperactive Wnt signaling. Cyld-/- mice are highly sensitive to skin tumor development under TPA or UV-B treatment. All of these types of evidence are consistent with a definitive relationship between the CYLD gene and Brooke-Spiegler syndrome.