MEF2C

Chr 5AD

myocyte enhancer factor 2C

Also known as: C5DELq14.3, DEL5q14.3, NEDHSIL

NCBI Gene: 4208 ENSG00000081189 UniProt: Q06413 OMIM: 600662

MEF2C encodes a transcription factor that regulates muscle-specific gene expression and plays crucial roles in cardiac development, neuronal development, and synaptic transmission in the hippocampus and neocortex. Mutations cause autosomal dominant neurodevelopmental disorder characterized by severe intellectual disability, epilepsy, stereotypic hand movements, hypotonia, and impaired language development. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.608), and deletions encompassing this locus cause chromosome 5q14.3 deletion syndrome with overlapping features.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.612 OMIM phenotypes

Clinical Summary— MEF2C

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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ClinVar Variants

60 unique Pathogenic / Likely Pathogenic· 95 VUS of 300 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint

0.61LOEUF

pLI 0.017

Z-score 2.91

OE 0.32 (0.18–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

3.95Z-score

OE missense 0.34 (0.29–0.40)

96 obs / 283.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.32 (0.18–0.61)

0≤0.351.4

Missense OE0.34 (0.29–0.40)

0≤0.61.4

Synonymous OE0.84

0≤1.21.6

LoF obs/exp: 7 / 21.6Missense obs/exp: 96 / 283.2Syn Z: 1.37

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMEF2C-related intellectual developmental disorder, stereotypic movements, epilepsy and/or cerebral malformationsLOFAD

0.75top 25%

GOF

0.3690th %ile

LOF

0.56top 25%

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

LOF1 literature citation · 45% of P/LP variants are LoF

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNFurthermore, dominant-negative mutant proteins of either Gli2 or MEF2C repressed each other's expression, while impairing cardiomyogenesis in P19 EC cells.PMID:22199256

LOFMEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathwaysPMID:23389741

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.