Description |
Case-level, family segregation, or case-control data that support the gene-disease association
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Gene-level experimental evidence that support the gene-disease association |
Sum of Genetic & Experimental
Evidence
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> 2 pubs w/ convincing evidence over time (>3 yrs) |
EVIDENCE SUMMARY |
MEF2C was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2010 (Le Meur et al., 2010 PMID:19592390; Zweier et al., 2010 PMID:20513142). At least 14 unique variants (e.g. missense, nonsense, frameshift, small deletions, and large deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 14 cases, in 7 publications (PMIDs: 19592390, 20513142, 23001426, 23389741, 27255693, 28794905, 30376817). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease appears to be de novo, loss of function. MEF2C is associated with the following disease entities per OMIM: (1) Chromosome 5q14.3 deletion syndrome (MIM:613443); and (2) Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations (MIM:613443). Note that these two disease entities share the same MIM number indicating they may be the same disease. However, per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we found that the Chromosome 5q14.3 deletion syndrome is a contiguous gene deletion syndrome involving multiple genes of interest beyond MEF2C, including the gene RASA1, exemplifying different molecular mechanisms. Furthermore, the Chromosome 5q14.3 deletion syndrome is associated with a skin phenotype that is not found in individuals with isolated variation in the MEF2C gene. Therefore, we have split into two disease entities; this curation represents the relationship between MEF2C and Complex Neurodevelopmental disorder (MONDO:0100038) (intellectual disability, stereotypic movements, epilepsy, and/or cerebral malformations phenotype) only, in accordance to assertions made in the literature (Paciorkowski et al., 2013 PMID:23389741). This gene-disease association is supported by biochemical function, expression studies, and animal models. In summary, MEF2C is DEFINITIVELY associated with autosomal dominant complex neurodevelopmental 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 ClinGen Autism and Intellectual Disability Gene Curation Expert Panel on February 6, 2019 (SOP Version 6).
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