Gene Validity Curation

GNAO1 - movement disorder

Gene: GNAO1 (HGNC:4389)
Classification - 02/19/2019
Disease: movement disorder (MONDO_0005395)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Epilepsy EP
Evidence Summary: GNAO1 was first reported in relation to autosomal dominant (AD) rare genetic movement disorder in 2016 [Saitsu et al., PMID:25966631]. At least 10 unique variants have been reported in humans. These are all missense variants except for one variant that is predicted to result in loss of a splice donor. Evidence supporting this gene-disease relationship includes case-level data. All probands had hypotonia, developmental and motor delay, movement disorder, intellectual disability, and no to very limited speech. Some probands (6/20, 30%) had seizures, usually focal and well-controlled on anti-epileptic drugs. Many patients ( 8/20, 40%) had abnormal MRI or brain atrophy. There are many recurrent variants at two major residues: p.Arg209 and p.Glu246. This is because both of these sites are CpG sites that are prone to mutation. Variants identified include p.Arg209His, p.Arg209Gly, p.Arg209Cys, p.Arg209Leu, p.Glu246Lys and p.Glu246Gly. Seven probands improved with placement of deep brain stimulators into the bilateral internal globus pallidus (29758257). Variants in this gene have been reported in at least 20 probands in 7 publications. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease may be heterozygous gain-of-function (28747448), but more experimental evidence is needed. Of note, this gene has also been implicated in early-infantile epileptic encephalopathy. This has been assessed separately. In summary, GNAO1 is definitively associated with AD rare genetic movement disorder. 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 Epilepsy Gene Curation Expert Panel on 2/19/2019 (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 19
36
12
Kulkarni N et al. 2016 Feb (PMID:26060304); Ananth AL et al. 2016 Jun (PMID:27068059); Saitsu H et al. 2016 Jan (PMID:25966631); Danti FR et al. 2017 Apr (PMID:28357411); Okumura A et al. 2018 Nov (PMID:29935962); Menke LA et al. 2016 Dec (PMID:27625011);
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
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
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) 0

 


 

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 0 12 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
10/03/2019
EXPERT CURATION (DATE)
Definitive
02/19/2019
EVIDENCE SUMMARY
GNAO1 was first reported in relation to autosomal dominant (AD) rare genetic movement disorder in 2016 [Saitsu et al., PMID:25966631]. At least 10 unique variants have been reported in humans. These are all missense variants except for one variant that is predicted to result in loss of a splice donor. Evidence supporting this gene-disease relationship includes case-level data. All probands had hypotonia, developmental and motor delay, movement disorder, intellectual disability, and no to very limited speech. Some probands (6/20, 30%) had seizures, usually focal and well-controlled on anti-epileptic drugs. Many patients ( 8/20, 40%) had abnormal MRI or brain atrophy. There are many recurrent variants at two major residues: p.Arg209 and p.Glu246. This is because both of these sites are CpG sites that are prone to mutation. Variants identified include p.Arg209His, p.Arg209Gly, p.Arg209Cys, p.Arg209Leu, p.Glu246Lys and p.Glu246Gly. Seven probands improved with placement of deep brain stimulators into the bilateral internal globus pallidus (29758257). Variants in this gene have been reported in at least 20 probands in 7 publications. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease may be heterozygous gain-of-function (28747448), but more experimental evidence is needed. Of note, this gene has also been implicated in early-infantile epileptic encephalopathy. This has been assessed separately. In summary, GNAO1 is definitively associated with AD rare genetic movement disorder. 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 Epilepsy Gene Curation Expert Panel on 2/19/2019 (SOP Version 6).