Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ARX : early infantile epileptic encephalopathy

HGNC:18060 | MONDO_0016021
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Epilepsy
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 6
9.5
9.5
Ortega-Moreno L et al. 2017 Nov 30 (PMID:29190809); Mirzaa GM et al. 2013 May (PMID:23583054); Kwong AK et al. 2015 May 7 (PMID:25951140); Wallerstein R et al. 2008 Jun (PMID:18462864);
Proband with predicted or proven null variant 1.5 0-2 10 17 2 2
Mirzaa GM et al. 2013 May (PMID:23583054); Wallerstein R et al. 2008 Jun (PMID:18462864); Lindy AS et al. 2018 May (PMID:29655203); Butler KM et al. 2017 Dec (PMID:29056246);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 3
0
0
Lee CG et al. 2018 Jun 20 (PMID:29924869); Wallerstein R et al. 2008 Jun (PMID:18462864); Lindy AS et al. 2018 May (PMID:29655203);
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) 11.5
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
0
Non-patient cells 0.5 0 - 1 1 0
Marsh E et al. 2009 Jun (PMID:19439424);
Models Non-human model organism 2 0 - 4 4 1 2 2
Marsh E et al. 2009 Jun (PMID:19439424);
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) 2

 


 

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 11.5 2 13.5 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
06/21/2019
EXPERT CURATION (DATE)
Definitive
06/21/2019
EVIDENCE SUMMARY
ARX was reported in relation to Early Infantile Epileptic Encephalopathy in 2002 (Stromme et al. 2002). It is also reported in relation to intellectual disability (syndromic and nonsyndromic), hydranencephaly with abnormal genitalia, X-linked Lissencephaly, Partington syndrome, and Proud syndrome. Evidence included in this curation excluded individuals with syndromic diagnoses and/or intellectual disability. At least 18 unique variants (missense, in-frame indel, nonsense, frameshift and polyalanine repeat, etc.) have been reported in humans. Evidence supporting this gene-disease pair includes case-level data and experimental data. In summary, ARX is definitively associated with X-linked Early Infantile Epileptic Encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on 6/4/19 (SOP version 6).