Gene Validity Curation

CHRNA4 - epilepsy, nocturnal frontal lobe

Gene: CHRNA4 (HGNC:1958)
Classification - 02/18/2020
Disease: epilepsy, nocturnal frontal lobe (MONDO_0000030)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Epilepsy EP
Evidence Summary: CHRNA4 was reported in relation to autosomal dominant nocturnal frontal lobe epilepsy in 1995 (PMID: 7550350). At least 7 unique variants (missense, small insertion) have been reported in humans. "So far, nearly all of the AD nocturnal frontal lobe epilepsy mutations identified within CHRNA4 are missense mutations that cause amino acid exchanges within the second, less often the first, transmembrane domain" (PMID: 25194481). This gene-disease relationship is supported by case-level data and experimental data including functional alteration studies and a mouse model. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. In summary, CHRNA4 is definitively associated with autosomal dominant nocturnal frontal lobe epilepsy.
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 3
6
6
Wang MY et al. 2014 Dec (PMID:25282705); Sansoni V et al. 2012 Jun (PMID:22118295); Phillips HA et al. 2000 Aug (PMID:10939581);
Proband with predicted or proven null variant 1.5 0-2 10 1 2 2
Steinlein OK et al. 1997 Jun (PMID:9175743);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 7
2.6
2.6
El Helou J et al. 2008 Oct (PMID:18762450); Steinlein OK et al. 1995 Oct (PMID:7550350); Hirose S et al. 1999 Nov 10 (PMID:10563623); Leniger T et al. 2003 Jul (PMID:12823585); Rozycka A et al. 2003 Aug (PMID:12887446); Chen Y et al. 2009 Feb (PMID:19058950); Cho YW et al. 2003 Nov (PMID:14623738);
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 1.5 1.5  
Candidate gene sequencing 11.7 2
Steinlein OK et al. 1995 Oct (PMID:7550350); Cho YW et al. 2003 Nov (PMID:14623738);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 11.7    
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
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 3 0
Steinlein OK et al. 2012 Mar (PMID:22036597); Steinlein OK et al. 1997 Jun (PMID:9175743);
Models Non-human model organism 2 0 - 4 4 1 2 2
Klaassen A et al. 2006 Dec 12 (PMID:17146052);
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 12 2 14 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
02/26/2020
EXPERT CURATION (DATE)
Definitive
02/18/2020
EVIDENCE SUMMARY
CHRNA4 was reported in relation to autosomal dominant nocturnal frontal lobe epilepsy in 1995 (PMID: 7550350). At least 7 unique variants (missense, small insertion) have been reported in humans. "So far, nearly all of the AD nocturnal frontal lobe epilepsy mutations identified within CHRNA4 are missense mutations that cause amino acid exchanges within the second, less often the first, transmembrane domain" (PMID: 25194481). This gene-disease relationship is supported by case-level data and experimental data including functional alteration studies and a mouse model. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. In summary, CHRNA4 is definitively associated with autosomal dominant nocturnal frontal lobe epilepsy.