Gene Validity Curation

MED23 - syndromic intellectual disability

Gene: MED23 (HGNC:2372)
Classification - 04/01/2020
Disease: syndromic intellectual disability (MONDO_0000508)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism EP
Evidence Summary: MED23 was first reported in relation to non-syndromic autosomal recessive intellectual disability in 2011 (Hashimoto et al. PMID 21868677). Though MED23 was initially associated with non-syndromic intellectual disability, as the number of probands reported in the literature has increased, a consistent phenotypic profile has been appreciated among reported probands, including early onset epilepsy, spasticity, microcephaly and, less frequently, delayed myelination and thin corpus callosum. For this reason, syndromic intellectual disability was selected as the disease entity for MED23 curation. The gene disease relationship is supported by case-level, segregation and experimental data. Variants in MED23 have been reported in 11 affected individuals from 6 unrelated families, 4 with homozygous missense variants and 2 with compound heterozygous variants in trans (a total of 1 nonsense and 7 missense variants) in 6 publications (PMIDs 21868677, 25845469, 27311965, 27457812, 30847200, 31164858). Variants in this gene segregate with disease in at least one family (PMID 21868677). It has been shown that loss of function variants in MED23 and other mediator complex subunits are linked to neurological disorders specifically through transcriptional dysregulation of target genes (PMID 21868677). Missense variants that are shown to result in protein loss of function through dysregulation of specific target genes expression in an assay using patient cells were scored equal to the number of points awarded to putative null variants. The gene-disease relationship is supported by a number of functional studies including non-human model organism (PMID 19417216), biochemical (PMID 11934987), and rescue experiments (PMID 21868677). In summary, the available evidence of gene-disease relationship is convincing due to phenotypic similarities observed in 4 of the families and in particular mutations in other genes encoding subunits of the Mediator kinase module (MED12, MED13, MED13L and CDK8: PMIDs 6711603, 17369503, 29740699, 24781760, 30905399) have been shown to be involved in ID/ASD, however, additional genetic and/or experimental data is needed to reach a score sufficient for classification of “Definitive”. Currently, there is moderate evidence to support the relationship between MED23 with autosomal recessive syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 4/1/20 (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
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 2
5
6.75
Hashimoto S et al. 2011 Aug 26 (PMID:21868677); Trehan A et al. 2015 Jun (PMID:25845469);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 4
1.75
Lionel AC et al. 2016 Sep (PMID:27311965); Hashemi-Gorji F et al. 2019 Feb (PMID:30847200); Demos M et al. 2019 May 21 (PMID:31164858); Riazuddin S et al. 2017 Nov (PMID:27457812);
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing 4.16 1
Hashimoto S et al. 2011 Aug 26 (PMID:21868677);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 4.16    
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) 7.75
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
1
1.5
Stevens JL et al. 2002 Apr 26 (PMID:11934987);
Protein Interaction 0.5 0 - 2 1 0.5
Hashimoto S et al. 2011 Aug 26 (PMID:21868677);
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 1 0.5 1
Balamotis MA et al. 2009 May 5 (PMID:19417216);
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 1 0.5
Hashimoto S et al. 2011 Aug 26 (PMID:21868677);
Total Experimental Evidence Points (Maximum 6) 2.5

 


 

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 7.75 2.5 10.25 NO
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
05/21/2020
EXPERT CURATION (DATE)
Moderate
04/01/2020
EVIDENCE SUMMARY
MED23 was first reported in relation to non-syndromic autosomal recessive intellectual disability in 2011 (Hashimoto et al. PMID 21868677). Though MED23 was initially associated with non-syndromic intellectual disability, as the number of probands reported in the literature has increased, a consistent phenotypic profile has been appreciated among reported probands, including early onset epilepsy, spasticity, microcephaly and, less frequently, delayed myelination and thin corpus callosum. For this reason, syndromic intellectual disability was selected as the disease entity for MED23 curation. The gene disease relationship is supported by case-level, segregation and experimental data. Variants in MED23 have been reported in 11 affected individuals from 6 unrelated families, 4 with homozygous missense variants and 2 with compound heterozygous variants in trans (a total of 1 nonsense and 7 missense variants) in 6 publications (PMIDs 21868677, 25845469, 27311965, 27457812, 30847200, 31164858). Variants in this gene segregate with disease in at least one family (PMID 21868677). It has been shown that loss of function variants in MED23 and other mediator complex subunits are linked to neurological disorders specifically through transcriptional dysregulation of target genes (PMID 21868677). Missense variants that are shown to result in protein loss of function through dysregulation of specific target genes expression in an assay using patient cells were scored equal to the number of points awarded to putative null variants. The gene-disease relationship is supported by a number of functional studies including non-human model organism (PMID 19417216), biochemical (PMID 11934987), and rescue experiments (PMID 21868677). In summary, the available evidence of gene-disease relationship is convincing due to phenotypic similarities observed in 4 of the families and in particular mutations in other genes encoding subunits of the Mediator kinase module (MED12, MED13, MED13L and CDK8: PMIDs 6711603, 17369503, 29740699, 24781760, 30905399) have been shown to be involved in ID/ASD, however, additional genetic and/or experimental data is needed to reach a score sufficient for classification of “Definitive”. Currently, there is moderate evidence to support the relationship between MED23 with autosomal recessive syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 4/1/20 (SOP Version 7).