Gene Validity Curation

MAOA - Brunner syndrome

Gene: MAOA (HGNC:6833)
Classification - 04/14/2020
Disease: Brunner syndrome (MONDO_0010379)
Mode of Inheritance: X-linked inheritance (HP:0001417)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism EP
Evidence Summary: MAOA was first associated with disease in 1993 in a large Dutch family with 14 individuals (consistent with X-linked inheritance) affected by Brunner syndrome. Brunner syndrome is characterized by borderline intellectual disability (ID), prominent behavioral abnormalities including aggressive and violent behavior, and deficiency of monoamine oxidase A enzymatic activity as shown by Brunner et al in 1993 (PMIDs 8211186, 8503438). The gene-disease relationship includes case-level, segregation and experimental data. Loss of function variants in the MAOA coding region have been reported in at least 6 probands (3 nonsense, splice, frameshift and 3 missense) in 5 publications (PMIDs 8211186, 24169519, 25969726, 25807999, 29158550). Variants in this gene segregate with disease in at least 1 large family (PMID 8211186) and 2 siblings (PMID: 25969726, 25807999).The maximum genetic evidence score was reached after awarding missense variants with supporting biochemical evidence (loss of MAOA enzymatic activity) 1.5 points (equal to the number of points awarded to putative null variants), since deficiency of MAOA activity is a specific hallmark of loss of MAOA function. The gene-disease relationship is supported by a number of independent animal model studies including PMIDs 7792602 and 18418249. In summary, there is sufficient evidence to support definitive association between MAOA with Brunner syndrome. Although clinical diagnosis of Brunner syndrome is rare, the gene-disease association has been demonstrated in multiple reports and animal model studies that has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 1/15/20 (SOP Version 7).
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
Proband with predicted or proven null variant 1.5 0-2 10 3 4.5 4.5
Brunner HG et al. 1993 Oct 22 (PMID:8211186); Codina-Solà M et al. 2015 Apr 15 (PMID:25969726); Palmer EE et al. 2016 Jan (PMID:25807999);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 3
3.1
3.1
Piton A et al. 2014 Jun (PMID:24169519); Palmer EE et al. 2016 Jan (PMID:25807999); Popp B et al. 2017 Dec (PMID:29158550);
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 1  
Candidate gene sequencing 3.55 1
Brunner HG et al. 1993 Oct 22 (PMID:8211186);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.55    
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) 8.6
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
Kim JJ et al. 1997 May 27 (PMID:9159177);
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 2 4 4
Cases O et al. 1995 Jun 23 (PMID:7792602); Bortolato M et al. 2013 May (PMID:22850464);
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) 4.5

 


 

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 8.6 4.5 13.1 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
02/05/2020
EXPERT CURATION (DATE)
Definitive
04/14/2020
EVIDENCE SUMMARY
MAOA was first associated with disease in 1993 in a large Dutch family with 14 individuals (consistent with X-linked inheritance) affected by Brunner syndrome. Brunner syndrome is characterized by borderline intellectual disability (ID), prominent behavioral abnormalities including aggressive and violent behavior, and deficiency of monoamine oxidase A enzymatic activity as shown by Brunner et al in 1993 (PMIDs 8211186, 8503438). The gene-disease relationship includes case-level, segregation and experimental data. Loss of function variants in the MAOA coding region have been reported in at least 6 probands (3 nonsense, splice, frameshift and 3 missense) in 5 publications (PMIDs 8211186, 24169519, 25969726, 25807999, 29158550). Variants in this gene segregate with disease in at least 1 large family (PMID 8211186) and 2 siblings (PMID: 25969726, 25807999).The maximum genetic evidence score was reached after awarding missense variants with supporting biochemical evidence (loss of MAOA enzymatic activity) 1.5 points (equal to the number of points awarded to putative null variants), since deficiency of MAOA activity is a specific hallmark of loss of MAOA function. The gene-disease relationship is supported by a number of independent animal model studies including PMIDs 7792602 and 18418249. In summary, there is sufficient evidence to support definitive association between MAOA with Brunner syndrome. Although clinical diagnosis of Brunner syndrome is rare, the gene-disease association has been demonstrated in multiple reports and animal model studies that has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 1/15/20 (SOP Version 7).