Gene Validity Curation

ITK - lymphoproliferative syndrome 1

Gene: ITK (HGNC:6171)
Classification - 11/21/2019
Disease: lymphoproliferative syndrome 1 (MONDO_0013081)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP
Evidence Summary: There is sufficient evidence published associating the ITK gene with lymphoproliferative syndrome 1 since the gene-disease relationship was firstly proposed by Huck et al (2009). Multiple studies of case level have been performed with patients with lymphoproliferative syndrome 1 that have biallelic loss of function variants in the ITK gene. ITK-/- mouse model has been established to recap partial patients’ phenotypes including decreased number of natural killer T cells. Lymph nodes from patients were found with significantly decreased ITK immunoreactivity compared with normal controls. All of these evidence suggest a definitive relationship between the ITK gene and lymphoproliferative syndrome 1.
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
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 5
10
12
Stepensky P et al. 2011 Mar (PMID:21109689); Linka RM et al. 2012 May (PMID:22289921); Alme C et al. 2015 Oct (PMID:26056787); Mansouri D et al. 2012 Apr 5 (PMID:22487848); Serwas NK et al. 2014 Jul 24 (PMID:25061172);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
2
Huck K et al. 2009 May (PMID:19425169); Linka RM et al. 2012 May (PMID:22289921);
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing 1.7 1
Stepensky P et al. 2011 Mar (PMID:21109689);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.7    
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
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Huck K et al. 2009 May (PMID:19425169);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Huck K et al. 2009 May (PMID:19425169);
Models Non-human model organism 2 0 - 4 4 1 2 4
Bachmann MF et al. 1997 Oct (PMID:9311799);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Linka RM et al. 2012 May (PMID:22289921);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 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 12 5 17 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
10/02/2019
EXPERT CURATION (DATE)
Definitive
11/21/2019
EVIDENCE SUMMARY
There is sufficient evidence published associating the ITK gene with lymphoproliferative syndrome 1 since the gene-disease relationship was firstly proposed by Huck et al (2009). Multiple studies of case level have been performed with patients with lymphoproliferative syndrome 1 that have biallelic loss of function variants in the ITK gene. ITK-/- mouse model has been established to recap partial patients’ phenotypes including decreased number of natural killer T cells. Lymph nodes from patients were found with significantly decreased ITK immunoreactivity compared with normal controls. All of these evidence suggest a definitive relationship between the ITK gene and lymphoproliferative syndrome 1.