Gene Validity Curation

ARHGEF9 - complex neurodevelopmental disorder

Gene: ARHGEF9 (HGNC:14561)
Classification - 11/21/2019
Disease: complex neurodevelopmental disorder (MONDO_0100038)
Mode of Inheritance: X-linked inheritance (HP:0001417)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism EP
Evidence Summary: ARHGEF9 was first reported in relation to complex neurodevelopmental disorder in 2004, at which time Harvey et al. (PMID: 15215304) reported a missense variant in a patient with hyperekplexia, severe ID, and severe epilepsy. Functional studies suggested that the variant (G55A) disrupted critical domains in the protein, preventing appropriate translocation of the synaptic scaffold, gephyrin, to the cell membrane. At least 132 pathogenic/likely pathogenic have been reported in humans. The majority of these variants have been SNVs, deletions, or duplications. Both case-level and experimental evidence support this gene-disease relationship. Summary of Case Level Data: 9.85 points Variants in this gene have been reported in more than 10 probands in the 8 publications presented in this curation (PMIDs: 15215304, 17893116, 21633362, 22612257, 26834553, 28589176, 29130122, 30914922). In multiple cases, the variant segregates with the disease phenotype in numerous affected family members (lack of proper genotyping prevents segregation data from being included). It should be noted that only 6.35 points worth of Case-Level Data could be included in the GCI. One case with a de novo paracentric inversion (Marco et al., PMID: 17893116, and another case with a de novo 737-kb microdeletion (Shimojima et al., PMID: 21633362) were also counted towards the Case Level evidence (scoring the de novo default of 2 pts and 1.5 pts, respectively, for a total of 3.5 additional points), but could not be scored in the GCI. Experimental Evidence: 2 points This gene-disease relationship is also supported by Functional (Biochemical function), Functional alteration (Patient cells), and Functional alteration (Non-patient cells) (PMIDs: 15215304, 25898924, 25678704) In summary, there is sufficient evidence to apply a moderate classification to this gene-disease relationship.
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 1
1.5
1.5
Alber M et al. 2017 Jun (PMID:28589176);
Proband with predicted or proven null variant 1.5 0-2 10 3 3.5 3.5
Shimojima K et al. 2011 Aug (PMID:21633362); Long P et al. 2016 Jan 20 (PMID:26834553); Chiou TT et al. 2019 Mar 12 (PMID:30914922);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 4
1.35
1.35
Harvey K et al. 2004 Jun 23 (PMID:15215304); Lemke JR et al. 2012 Aug (PMID:22612257); Alber M et al. 2017 Jun (PMID:28589176); Wang JY et al. 2018 Jan (PMID:29130122);
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) 6.35
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
0.5
Harvey K et al. 2004 Jun 23 (PMID:15215304);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
1.5
Machado CO et al. 2016 Jan (PMID:25898924);
Non-patient cells 0.5 0 - 1 1 0.5
Papadopoulos T et al. 2015 Mar 27 (PMID:25678704);
Models Non-human model organism 2 0 - 4 4
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 6.35 2 8.35 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)
Moderate
11/15/2019
EXPERT CURATION (DATE)
Moderate
11/21/2019
EVIDENCE SUMMARY
ARHGEF9 was first reported in relation to complex neurodevelopmental disorder in 2004, at which time Harvey et al. (PMID: 15215304) reported a missense variant in a patient with hyperekplexia, severe ID, and severe epilepsy. Functional studies suggested that the variant (G55A) disrupted critical domains in the protein, preventing appropriate translocation of the synaptic scaffold, gephyrin, to the cell membrane. At least 132 pathogenic/likely pathogenic have been reported in humans. The majority of these variants have been SNVs, deletions, or duplications. Both case-level and experimental evidence support this gene-disease relationship. Summary of Case Level Data: 9.85 points Variants in this gene have been reported in more than 10 probands in the 8 publications presented in this curation (PMIDs: 15215304, 17893116, 21633362, 22612257, 26834553, 28589176, 29130122, 30914922). In multiple cases, the variant segregates with the disease phenotype in numerous affected family members (lack of proper genotyping prevents segregation data from being included). It should be noted that only 6.35 points worth of Case-Level Data could be included in the GCI. One case with a de novo paracentric inversion (Marco et al., PMID: 17893116, and another case with a de novo 737-kb microdeletion (Shimojima et al., PMID: 21633362) were also counted towards the Case Level evidence (scoring the de novo default of 2 pts and 1.5 pts, respectively, for a total of 3.5 additional points), but could not be scored in the GCI. Experimental Evidence: 2 points This gene-disease relationship is also supported by Functional (Biochemical function), Functional alteration (Patient cells), and Functional alteration (Non-patient cells) (PMIDs: 15215304, 25898924, 25678704) In summary, there is sufficient evidence to apply a moderate classification to this gene-disease relationship.