Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CASK : X-linked syndromic intellectual disability

HGNC:1497 | MONDO_0020119
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Intellectual Disability and Autism
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 14
23.1
12
Najm J et al. 2008 Sep (PMID:19165920); Moog U et al. 2011 Nov (PMID:21954287); Hayashi S et al. 2012 Jan (PMID:21735175); Moog U et al. 2015 Apr 12 (PMID:25886057);
Proband with predicted or proven null variant 1.5 0-2 10 3 1.7 1.7
Moog U et al. 2011 Nov (PMID:21954287); Hayashi S et al. 2012 Jan (PMID:21735175);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
0.1
0.1
Moog U et al. 2011 Nov (PMID:21954287);
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  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 4 5.5 4
Atasoy D et al. 2007 Feb 13 (PMID:17287346); Srivastava S et al. 2016 Mar 31 (PMID:27036546); Huang TN et al. 2017 Jan (PMID:28234597); Liang C et al. 2017 Oct 1 (PMID:29067402);
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) 4

 


 

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 4 16 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
07/08/2019
EXPERT CURATION (DATE)
Definitive
07/09/2019
EVIDENCE SUMMARY
The CASK gene, which encodes a synaptic scaffolding protein, has been associated with X-linked syndromic intellectual disability using the ClinGen Clinical Validity Framework as of 7/3/2019. This association was made using both case-level genetic evidence, as well as experimental data. It should be noted that there are additional cases available in the literature, however, the four publications presented here surpass the cut-off for genetic evidence. Some cases could not be scored on the GCI due to variants extending larger than 10kb (see Moog et al., 2011 (PMID: 21954287) and Moog et al., 2015 (PMID: 25886057)). The large number of cases with variants in ClinVar or the ClinGen Allele Registry allowed for scoring cut-offs to be reached, even without including these cases. This association is supported by mouse models that recapitulate the phenotype expressed in humans, though relatively few CASK animal models have been studied. In summary, CASK is definitively associated with X-linked syndromic intellectual disability.