MEF2C

protein-coding

myocyte enhancer factor 2C, the group of Myocyte enhancer factor 2 proteins|MADS box family

Gene summary

This locus encodes a member of the MADS box transcription enhancer factor 2 (MEF2) family of proteins, which play a role in myogenesis. The encoded protein, MEF2 polypeptide C, has both trans-activating and DNA binding activities. This protein may play a role in maintaining the differentiated state of muscle cells. Mutations and deletions at this locus have been associated with severe cognitive disability, stereotypic movements, epilepsy, and cerebral malformation. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2010]

MANE transcript

NM_002397.5

Inheritance

ClinVar variants

P:125U:186B:171

Top phenotype

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr5:88,717,117-88,904,257

External References & Databases

Ensembl (ENSG00000081189)

Transcript & Mutation Effects

hg38 • Region Span ~187.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired languageSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013266

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: PanelApp Australia

neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired languageMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013266

Submitter: Ambry Genetics

neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired languageDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013266

Submitter: Ambry Genetics

neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired languageDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013266

Submitter: G2P

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*MEF2C* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2010 (Le Meur et al., PMID: 19592390; Zweier et al., PMID: 20513142). *MEF2C*-related disorder is characterized by moderate-to-profound developmental delay and intellectual disability, hypotonia, dysmorphic features, seizures, autistic features, stereotypic movements, severely impaired or absent speech, sleep issues, inability to walk independently, and visual, cardiac, and neuroimaging abnormalities. The disorder is typically caused by *de novo* variants, including missense, nonsense, frameshift, and small or large deletions. *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 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 concerns the relationship between *MEF2C* and complex neurodevelopmental disorder, in accordance to assertions made in the literature (Paciorkowski et al., 2013, PMID: 23389741). Fourteen variants (missense, nonsense, and frameshift) that have been reported in 14 probands in 7 publications (PMIDs: 19592390, 20513142, 23001426, 23389741, 27255693, 28794905, 30376817) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by biochemical function, expression studies, and animal models. In summary, there is definitive evidence supporting the relationship between *MEF2C* and 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 Intellectual Disability and Autism Gene Curation Expert Panel on February 6, 2019 (SOP Version 6).

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired languageAD

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 19876902; 19592390; 20412115; 20513142; 23001426

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MEF2C variants in ClinVar

17 Conditions Cataloged

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired languageTotal: 443

not providedTotal: 160

not specifiedTotal: 58

Inborn genetic diseasesTotal: 48

MEF2C-related disorderTotal: 21

Autism spectrum disorderTotal: 4

Intellectual disabilityTotal: 4

SeizureTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002397.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	3 clinvar	132 clinvar	1 clinvar	137
missense	9 clinvar	29 clinvar	163 clinvar	25 clinvar	11 clinvar	237
nonsense	13 clinvar	8 clinvar	9 clinvar	1 clinvar		31
start loss		3 clinvar				3
frameshift	33 clinvar	6 clinvar	7 clinvar			46
splice donor/acceptor (+/-2bp)	14 clinvar	9 clinvar	4 clinvar	1 clinvar		28
Total	69	56	186	159	12	482

Highest pathogenic variant AF is 0.00008311947

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 257 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002397.5	RefSeq	NP_002388.2	10	MANE Select
ENST00000504921.7	Ensembl	ENSP00000421925.5	10	MANE Select
NM_001131005.2	RefSeq	NP_001124477.1	9	Standard
NM_001193347.1	RefSeq	NP_001180276.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mef2ca	Danio rerio	Structure: cardiac muscle cell Quality: undifferentiated abnormal

Gene / Model

Organism

Observed Phenotype

mef2ca

Danio rerio

Structure: cardiac muscle cell

Quality: undifferentiated

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Oxytocin signaling pathway - Homo sapiens (human)
Apelin signaling pathway - Homo sapiens (human)
Fluid shear stress and atherosclerosis - Homo sapiens (human)
MAPK signaling pathway - Homo sapiens (human)
Transcriptional misregulation in cancer - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
MAPK cascade
blood vessel development
osteoblast differentiation
neuron migration

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
RNA polymerase II distal enhancer sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
cytoplasm
sarcoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000340208
Coding exons: 10
Length: 185948
Individuals with no LoFs: 124637
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 124654
p: 0.0000682

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.95	96	283	0.339	0.0000165	3144
Missense (PolyPhen)		36	151.56	0.23753		1720
Synonymous	1.37	95	114	0.837	0.00000757	952
Loss of Function	2.91	7	21.6	0.324	0.00000124	260

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000080	0.000080	rare
South Asian	0.00020	0.00020	rare
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription activator which binds specifically to the MEF2 element present in the regulatory regions of many muscle- specific genes. Controls cardiac morphogenesis and myogenesis, and is also involved in vascular development. Plays an essential role in hippocampal-dependent learning and memory by suppressing the number of excitatory synapses and thus regulating basal and evoked synaptic transmission. Crucial for normal neuronal development, distribution, and electrical activity in the neocortex. Necessary for proper development of megakaryocytes and platelets and for bone marrow B-lymphopoiesis. Required for B-cell survival and proliferation in response to BCR stimulation, efficient IgG1 antibody responses to T-cell-dependent antigens and for normal induction of germinal center B-cells. May also be involved in neurogenesis and in the development of cortical architecture (By similarity). Isoform 3 and isoform 4, which lack the repressor domain, are more active than isoform 1 and isoform 2. {ECO:0000250|UniProtKB:Q8CFN5, ECO:0000269|PubMed:11904443, ECO:0000269|PubMed:15340086, ECO:0000269|PubMed:15831463, ECO:0000269|PubMed:15834131, ECO:0000269|PubMed:9069290, ECO:0000269|PubMed:9384584}.;
Disease: DISEASE: Mental retardation, autosomal dominant 20 (MRD20) [MIM:613443]: A disorder characterized by severe mental retardation, absent speech, hypotonia, poor eye contact and stereotypic movements. Dysmorphic features include high broad forehead with variable small chin, short nose with anteverted nares, large open mouth, upslanted palpebral fissures and prominent eyebrows. Some patients have seizures. {ECO:0000269|PubMed:19592390}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0941

Intolerance Scores

LoFtool: 0.391
RVIS EVS: 0.06
RVIS percentile EVS: 58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium