Gene Validity Curation

MEGF10 - early-onset myopathy-areflexia-respiratory distress-dysphagia syndrome

Gene: MEGF10 (HGNC:29634)
Classification - 01/27/2020
Disease: early-onset myopathy-areflexia-respiratory distress-dysphagia syndrome (MONDO_0013731)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Congenital Myopathies EP
Evidence Summary: MEGF10 was first reported in relation to autosomal recessive MEGF10-related myopathy, historically known as early-onset myopathy-areflexia-respiratory distress-dysphagia (EMARDD) in 2011 (Logan et al., PMID: 22101682). At least 11 variants (e.g. missense, nonsense, frameshift, deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least nine probands in four publications (PMIDs: 22101682, 22371254, 23453856, 27460346). Variants in this gene segregated with disease in two additional family members plus several sibling pairs. More evidence is available in the literature, but the maximum score for genetic evidence has been reached.The mechanism for disease is homozygous loss of function, with MEGF10 deficency reducing the proliferation and migration of muscle sattelite cells, impeding muscle repair, and supporting premature differentiation in myoblasts during development. Of note, this gene has also been implicated in a form of multiminicore myopathy with generally reduced phenotypic severity and later age of onset. This entity is considered part of the MEGF10-related myopathy spectrum. This gene-disease association is supported by two animal models, expression studies, biochemical function evidence, and myoblast alteration. Models in both zebrafish and mice displayed some phenotypes of MEGF10 myopathy, but were ultimately limited in scope. Expression data showed clear expression in myoblasts during development and sattelite cells in mature organisms further supporting the disease mechanism. Biochemical function studies demonstrated the MEGF10 pathogenic mechanism. Mouse myoblasts were altered and found to have reduced migration, proliferation, and premature differentiation in the absence of MEFG10. In summary, MEGF10 is definitively associated with autosomal recessive MEGF10-related myopathy. This has been demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Myopathies Working Group on 01/27/20 (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 8
14
12
Logan CV et al. 2011 Nov 20 (PMID:22101682); Takayama K et al. 2016 Sep (PMID:27460346); Pierson TM et al. 2013 Jun (PMID:23453856);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
1
Boyden SE et al. 2012 May (PMID:22371254);
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 2.08 1
Logan CV et al. 2011 Nov 20 (PMID:22101682);
Total Summed LOD Score 2.08    
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 1
0.5
1
Holterman CE et al. 2007 Dec 3 (PMID:18056409);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Holterman CE et al. 2007 Dec 3 (PMID:18056409);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Saha M et al. 2017 Aug 1 (PMID:28498977);
Models Non-human model organism 2 0 - 4 4 2 2.5 2.5
Saha M et al. 2017 Aug 1 (PMID:28498977); Boyden SE et al. 2012 May (PMID:22371254);
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

 


 

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 4 16 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
01/27/2020
EXPERT CURATION (DATE)
Definitive
01/27/2020
EVIDENCE SUMMARY
MEGF10 was first reported in relation to autosomal recessive MEGF10-related myopathy, historically known as early-onset myopathy-areflexia-respiratory distress-dysphagia (EMARDD) in 2011 (Logan et al., PMID: 22101682). At least 11 variants (e.g. missense, nonsense, frameshift, deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least nine probands in four publications (PMIDs: 22101682, 22371254, 23453856, 27460346). Variants in this gene segregated with disease in two additional family members plus several sibling pairs. More evidence is available in the literature, but the maximum score for genetic evidence has been reached.The mechanism for disease is homozygous loss of function, with MEGF10 deficency reducing the proliferation and migration of muscle sattelite cells, impeding muscle repair, and supporting premature differentiation in myoblasts during development. Of note, this gene has also been implicated in a form of multiminicore myopathy with generally reduced phenotypic severity and later age of onset. This entity is considered part of the MEGF10-related myopathy spectrum. This gene-disease association is supported by two animal models, expression studies, biochemical function evidence, and myoblast alteration. Models in both zebrafish and mice displayed some phenotypes of MEGF10 myopathy, but were ultimately limited in scope. Expression data showed clear expression in myoblasts during development and sattelite cells in mature organisms further supporting the disease mechanism. Biochemical function studies demonstrated the MEGF10 pathogenic mechanism. Mouse myoblasts were altered and found to have reduced migration, proliferation, and premature differentiation in the absence of MEFG10. In summary, MEGF10 is definitively associated with autosomal recessive MEGF10-related myopathy. This has been demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Myopathies Working Group on 01/27/20 (SOP Version 7).