Human Gene Module / Chromosome 5 / MEF2C

MEF2Cmyocyte enhancer factor 2C

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
19 / 54
Rare Variants / Common Variants
75 / 1
EAGLE Score
9.85
Moderate Learn More
Aliases
MEF2C, C5DELq14.3,  DEL5q14.3
Associated Syndromes
Autosomal dominant mental retardation syndrome-20
Chromosome Band
5q14.3
Associated Disorders
DD/NDD, ADHD, ID, EP, EPS, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Relevance to Autism

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay.

Molecular Function

The encoded protein is a transcription factor involved in diverse developmental processes including hematopoiesis, cardiogenesis and neurogenesis.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MEF2C (54 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Regulation of progenitor cell proliferation and granulocyte function by microRNA-223 Johnnidis JB , et al. (2008) No -
2 Recent Recommendation Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo Li H , et al. (2008) No -
3 Recent Recommendation Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection Flavell SW , et al. (2008) No -
4 Primary Refining the phenotype associated with MEF2C haploinsufficiency Novara F , et al. (2010) Yes MR, epilepsy
5 Recent Recommendation Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2 Pfeiffer BE , et al. (2010) No -
6 Recent Recommendation Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression Zweier M , et al. (2010) No -
7 Recent Recommendation Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders Mikhail FM , et al. (2011) No -
8 Support Patterns and rates of exonic de novo mutations in autism spectrum disorders Neale BM , et al. (2012) Yes -
9 Support Refining the phenotype associated with MEF2C point mutations Bienvenu T , et al. (2012) No Epilepsy, autistic behaviors
10 Support Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95 Tsai NP , et al. (2012) No -
11 Support MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways Paciorkowski AR , et al. (2013) No Stereotypies, absent speech
12 Support Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1 Carvill GL , et al. (2013) No ID, ASD, DD
13 Support Refining analyses of copy number variation identifies specific genes associated with developmental delay Coe BP , et al. (2014) Yes -
14 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
15 Support MEF2C haploinsufficiency syndrome: Report of a new MEF2C mutation and review Rocha H , et al. (2016) No Autistic features
16 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
17 Recent Recommendation Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c Chen YC , et al. (2016) No -
18 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
19 Support MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders Harrington AJ , et al. (2016) No -
20 Recent Recommendation The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No ASD
21 Support Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes Parrini E , et al. (2016) No ASD
22 Recent Recommendation Experience-Dependent and Differential Regulation of Local and Long-Range Excitatory Neocortical Circuits by Postsynaptic Mef2c Rajkovich KE , et al. (2016) No -
23 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No Macrocephaly, hypotonia
24 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
25 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies Hamdan FF , et al. (2017) No DD/ID
26 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection Pardias AF , et al. (2018) No -
27 Support Novel MEF2C point mutations in Chinese patients with Rett (-like) syndrome or non-syndromic intellectual disability: insights into genotype-phenotype correlation Wang J , et al. (2018) No Autistic features
28 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
29 Support Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations Zhou WZ , et al. (2019) Yes -
30 Support Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders Schluth-Bolard C , et al. (2019) No ASD
31 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes Xiong J , et al. (2019) Yes ID
32 Support Disruption of chromatin organisation causes MEF2C gene overexpression in intellectual disability: a case report Yauy K , et al. (2019) No DD, ADHD
33 Support MEF2C Hypofunction in Neuronal and Neuroimmune Populations Produces MEF2C Haploinsufficiency Syndrome-like Behaviors in Mice Harrington AJ et al. (2020) No ASD, stereotypy
34 Support Genes influenced by MEF2C contribute to neurodevelopmental disease via gene expression changes that affect multiple types of cortical excitatory neurons Cosgrove D et al. (2020) No -
35 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
36 Support - Liu L et al. (2021) No ASD, DD
37 Recent Recommendation - Wright CF et al. (2021) No ASD or autistic features, stereotypy
38 Support - Wan L et al. (2021) No Autistic features, stereotypy
39 Support - Pode-Shakked B et al. (2021) Yes -
40 Support - Mahjani B et al. (2021) Yes -
41 Support - Chen S et al. (2021) Yes Epilepsy/seizures
42 Support - Cooley Coleman JA et al. (2022) No ASD, epilepsy/seizures, stereotypy
43 Support - Zhou X et al. (2022) Yes -
44 Recent Recommendation - Mohajeri K et al. (2022) No -
45 Support - Yuan B et al. (2023) Yes -
46 Support - Sanchis-Juan A et al. (2023) No -
47 Recent Recommendation - Wei-Ke Li et al. (2024) Yes -
48 Recent Recommendation - Kuokuo Li et al. (2024) Yes -
49 Support - Sreetama Basu et al. (2024) Yes -
50 Support - Jennifer Y Cho et al. (2024) No -
51 Support - Tamam Khalaf et al. (2024) No ADHD
52 Support - Claire Ward et al. () Yes -
53 Highly Cited Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation Han J , et al. (1997) No -
54 Highly Cited Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C Lin Q , et al. (1997) No -
Rare Variants   (75)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - inversion De novo - - 27841880 Redin C , et al. (2016)
- - translocation De novo - - 31375103 Yauy K , et al. (2019)
- - translocation De novo - - 27841880 Redin C , et al. (2016)
- - translocation Unknown - - 27841880 Redin C , et al. (2016)
- - copy_number_loss De novo - - 20412115 Novara F , et al. (2010)
- - copy_number_loss De novo - - 20513142 Zweier M , et al. (2010)
- - copy_number_loss De novo - - 34022131 Wright CF et al. (2021)
- - insertion De novo - - 30923172 Schluth-Bolard C , et al. (2019)
- - copy_number_loss De novo - - 22031302 Mikhail FM , et al. (2011)
- - translocation De novo - - 30923172 Schluth-Bolard C , et al. (2019)
c.55-2A>G - splice_site_variant De novo - - 34055696 Wan L et al. (2021)
c.865-1G>T - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.-8C>T - 5_prime_UTR_variant De novo - - 34022131 Wright CF et al. (2021)
c.977C>A p.Ser326Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.-26C>T - 5_prime_UTR_variant De novo - - 34022131 Wright CF et al. (2021)
c.-66A>T - 5_prime_UTR_variant De novo - - 34022131 Wright CF et al. (2021)
c.1323C>G p.Tyr441Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
- - complex_structural_alteration De novo - - 27841880 Redin C , et al. (2016)
- - copy_number_loss Unknown Not maternal - 20412115 Novara F , et al. (2010)
- - copy_number_loss Unknown Not maternal - 20513142 Zweier M , et al. (2010)
c.-103G>A - 5_prime_UTR_variant De novo - - 34022131 Wright CF et al. (2021)
- - copy_number_loss De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.44G>C p.Arg15Pro missense_variant De novo - - 34055696 Wan L et al. (2021)
c.766C>T p.Arg256Ter stop_gained De novo - - 30763456 Zhou WZ , et al. (2019)
- p.Ter464SerextTer? stop_lost De novo - - 23708187 Carvill GL , et al. (2013)
c.43C>T p.Arg15Cys missense_variant De novo - - 33004838 Wang T et al. (2020)
c.58A>G p.Thr20Ala missense_variant De novo - - 33004838 Wang T et al. (2020)
c.44G>A p.Arg15His missense_variant De novo - - 36881370 Yuan B et al. (2023)
- - copy_number_loss Unknown - Unknown 23389741 Paciorkowski AR , et al. (2013)
c.116G>T p.Cys39Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.122G>A p.Cys41Tyr missense_variant De novo - - 34800434 Chen S et al. (2021)
c.259-213T>G - intron_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.1A>G p.Met1? initiator_codon_variant De novo - - 34055696 Wan L et al. (2021)
c.26C>T p.Thr9Met missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.258+5G>C - splice_site_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.1162T>A p.Ser388Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.122G>A p.Cys41Tyr missense_variant De novo - - 31031587 Xiong J , et al. (2019)
c.80G>C p.Gly27Ala missense_variant De novo - - 20513142 Zweier M , et al. (2010)
c.805-866_805-865dup - frameshift_variant De novo - - 34055696 Wan L et al. (2021)
- - copy_number_loss 2 de novo, 8 unknown - Unknown 25217958 Coe BP , et al. (2014)
c.113T>A p.Leu38Gln missense_variant De novo - - 20513142 Zweier M , et al. (2010)
c.51_54del p.Gln18Ter frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.766C>T p.Arg256Ter stop_gained De novo - Simplex 30376817 Wang J , et al. (2018)
c.108C>A p.Ser36Arg missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.71G>A p.Arg24Lys missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.9A>T p.Arg3Ser missense_variant Familial Maternal - 34055696 Wan L et al. (2021)
c.44G>C p.Arg15Pro missense_variant De novo - Simplex 33951346 Liu L et al. (2021)
c.115T>C p.Cys39Arg missense_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.78del p.Phe26LeufsTer3 frameshift_variant De novo - - 34055696 Wan L et al. (2021)
c.43C>T p.Arg15Cys missense_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.403-1G>T p.? splice_site_variant De novo - Simplex 30376817 Wang J , et al. (2018)
c.9A>T p.Arg3Ser missense_variant De novo - Simplex 27255693 Rocha H , et al. (2016)
c.90G>T p.Lys30Asn missense_variant De novo - - 32418612 Harrington AJ et al. (2020)
- - complex_structural_alteration De novo - - 30923172 Schluth-Bolard C , et al. (2019)
c.48C>G p.Asn16Lys missense_variant De novo - Simplex 30376817 Wang J , et al. (2018)
c.311A>C p.Asp104Ala missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.109G>A p.Val37Met missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.851del p.Thr284ArgfsTer5 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.3G>A p.Met1? initiator_codon_variant Familial Maternal - 34055696 Wan L et al. (2021)
c.1276C>G p.Arg426Gly missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.241A>G p.Asn81Asp missense_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.104T>C p.Leu35Pro missense_variant De novo - Simplex 38012399 Wei-Ke Li et al. (2024)
T>G - intergenic_variant Familial Both parents Multiplex 27667684 Doan RN , et al. (2016)
c.70dup p.Arg24LysfsTer11 frameshift_variant De novo - - 20513142 Zweier M , et al. (2010)
c.169T>G p.Tyr57Asp missense_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.65C>G p.Thr22Arg missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.334G>T p.Glu112Ter stop_gained Unknown Not paternal Simplex 30376817 Wang J , et al. (2018)
c.565C>T p.Arg189Ter stop_gained Unknown Not maternal Simplex 30376817 Wang J , et al. (2018)
c.226_236del p.His76AspfsTer18 frameshift_variant De novo - - 20513142 Zweier M , et al. (2010)
c.403-1G>T p.? splice_site_variant De novo - Multi-generational 30763456 Zhou WZ , et al. (2019)
c.137T>C p.Ile46Thr missense_variant Unknown Not maternal - 32418612 Harrington AJ et al. (2020)
c.397del p.Ala133LeufsTer52 frameshift_variant De novo - Simplex 23001426 Bienvenu T , et al. (2012)
c.773del p.Pro258HisfsTer11 frameshift_variant Unknown - Unknown 23389741 Paciorkowski AR , et al. (2013)
c.120_121insCTGTGA p.Asp40_Cys41insLeuTer inframe_insertion Familial Paternal - 32418612 Harrington AJ et al. (2020)
c.297del p.Asp100IlefsTer26 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
A>G - intergenic_variant - - - 29483656 Pardias AF , et al. (2018)
SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2021
1
icon
1

Score remained at 1

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay. Heterozygous mutations in MEF2C, as well as heterozygous 5q14.3 deletions involving MEF2C, are responsible for an autosomal dominant form of intellectual disability (MRD20, also referred to as chromosome 5q14.3 deletion syndrome; OMIM 613443), a disorder in which a subset of cases present with stereotypic/repetitive movements and autistic features (Zweier et al., 2010; Paciorkowski et al., 2013). Sequencing of balanced chromosomal abnormalities (BCAs) in 273 subjects with a spectrum of congenital anomalies identified BCA breakpoints in eight subjects that altered a single topologically associated domain (TAD) encompassing the MEF2C gene that reached genome-wide significance (P=8.0E-09); decreased MEF2C expression was observed in four subjects for whom RNA from LCLs was available (Redin et al., 2016). Conditional knockout of MEF2C in the cortical neurons of mice resulted in reduced cortical network activity, due in part to increased inhibitory and decreased excitatory synaptic transmission, as well as the onset of behaviors related to autism, intellectual disability, and schizophrenia (Harrington et al., 2016).

Reports Added
[Confirming the contribution and genetic spectrum of de novo mutation in infantile spasms: Evidence from a Chinese cohort2021] [Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms2021] [Genotypes and Phenotypes of MEF2C Haploinsufficiency Syndrome: New Cases and Novel Point Mutations2021]
10/1/2020
1
icon
1

Score remained at 1

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay. Heterozygous mutations in MEF2C, as well as heterozygous 5q14.3 deletions involving MEF2C, are responsible for an autosomal dominant form of intellectual disability (MRD20, also referred to as chromosome 5q14.3 deletion syndrome; OMIM 613443), a disorder in which a subset of cases present with stereotypic/repetitive movements and autistic features (Zweier et al., 2010; Paciorkowski et al., 2013). Sequencing of balanced chromosomal abnormalities (BCAs) in 273 subjects with a spectrum of congenital anomalies identified BCA breakpoints in eight subjects that altered a single topologically associated domain (TAD) encompassing the MEF2C gene that reached genome-wide significance (P=8.0E-09); decreased MEF2C expression was observed in four subjects for whom RNA from LCLs was available (Redin et al., 2016). Conditional knockout of MEF2C in the cortical neurons of mice resulted in reduced cortical network activity, due in part to increased inhibitory and decreased excitatory synaptic transmission, as well as the onset of behaviors related to autism, intellectual disability, and schizophrenia (Harrington et al., 2016).

Reports Added
[Genes influenced by MEF2C contribute to neurodevelopmental disease via gene expression changes that affect multiple types of cortical excitatory neurons2020] [Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
7/1/2020
1
icon
1

Score remained at 1

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay. Heterozygous mutations in MEF2C, as well as heterozygous 5q14.3 deletions involving MEF2C, are responsible for an autosomal dominant form of intellectual disability (MRD20, also referred to as chromosome 5q14.3 deletion syndrome; OMIM 613443), a disorder in which a subset of cases present with stereotypic/repetitive movements and autistic features (Zweier et al., 2010; Paciorkowski et al., 2013). Sequencing of balanced chromosomal abnormalities (BCAs) in 273 subjects with a spectrum of congenital anomalies identified BCA breakpoints in eight subjects that altered a single topologically associated domain (TAD) encompassing the MEF2C gene that reached genome-wide significance (P=8.0E-09); decreased MEF2C expression was observed in four subjects for whom RNA from LCLs was available (Redin et al., 2016). Conditional knockout of MEF2C in the cortical neurons of mice resulted in reduced cortical network activity, due in part to increased inhibitory and decreased excitatory synaptic transmission, as well as the onset of behaviors related to autism, intellectual disability, and schizophrenia (Harrington et al., 2016).

Reports Added
[MEF2C Hypofunction in Neuronal and Neuroimmune Populations Produces MEF2C Haploinsufficiency Syndrome-like Behaviors in Mice2020]
10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay. Heterozygous mutations in MEF2C, as well as heterozygous 5q14.3 deletions involving MEF2C, are responsible for an autosomal dominant form of intellectual disability (MRD20, also referred to as chromosome 5q14.3 deletion syndrome; OMIM 613443), a disorder in which a subset of cases present with stereotypic/repetitive movements and autistic features (Zweier et al., 2010; Paciorkowski et al., 2013). Sequencing of balanced chromosomal abnormalities (BCAs) in 273 subjects with a spectrum of congenital anomalies identified BCA breakpoints in eight subjects that altered a single topologically associated domain (TAD) encompassing the MEF2C gene that reached genome-wide significance (P=8.0E-09); decreased MEF2C expression was observed in four subjects for whom RNA from LCLs was available (Redin et al., 2016). Conditional knockout of MEF2C in the cortical neurons of mice resulted in reduced cortical network activity, due in part to increased inhibitory and decreased excitatory synaptic transmission, as well as the onset of behaviors related to autism, intellectual disability, and schizophrenia (Harrington et al., 2016).

Reports Added
[New Scoring Scheme]
7/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay. Heterozygous mutations in MEF2C, as well as heterozygous 5q14.3 deletions involving MEF2C, are responsible for an autosomal dominant form of intellectual disability (MRD20, also referred to as chromosome 5q14.3 deletion syndrome; OMIM 613443), a disorder in which a subset of cases present with stereotypic/repetitive movements and autistic features (Zweier et al., 2010; Paciorkowski et al., 2013). Sequencing of balanced chromosomal abnormalities (BCAs) in 273 subjects with a spectrum of congenital anomalies identified BCA breakpoints in eight subjects that altered a single topologically associated domain (TAD) encompassing the MEF2C gene that reached genome-wide significance (P=8.0E-09); decreased MEF2C expression was observed in four subjects for whom RNA from LCLs was available (Redin et al., 2016). Conditional knockout of MEF2C in the cortical neurons of mice resulted in reduced cortical network activity, due in part to increased inhibitory and decreased excitatory synaptic transmission, as well as the onset of behaviors related to autism, intellectual disability, and schizophrenia (Harrington et al., 2016).

Reports Added
[Disruption of chromatin organisation causes MEF2C gene overexpression in intellectual disability: a case report.2019]
4/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay. Heterozygous mutations in MEF2C, as well as heterozygous 5q14.3 deletions involving MEF2C, are responsible for an autosomal dominant form of intellectual disability (MRD20, also referred to as chromosome 5q14.3 deletion syndrome; OMIM 613443), a disorder in which a subset of cases present with stereotypic/repetitive movements and autistic features (Zweier et al., 2010; Paciorkowski et al., 2013). Sequencing of balanced chromosomal abnormalities (BCAs) in 273 subjects with a spectrum of congenital anomalies identified BCA breakpoints in eight subjects that altered a single topologically associated domain (TAD) encompassing the MEF2C gene that reached genome-wide significance (P=8.0E-09); decreased MEF2C expression was observed in four subjects for whom RNA from LCLs was available (Redin et al., 2016). Conditional knockout of MEF2C in the cortical neurons of mice resulted in reduced cortical network activity, due in part to increased inhibitory and decreased excitatory synaptic transmission, as well as the onset of behaviors related to autism, intellectual disability, and schizophrenia (Harrington et al., 2016).

Reports Added
[Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with develop...2019] [Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.2019]
1/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay. Heterozygous mutations in MEF2C, as well as heterozygous 5q14.3 deletions involving MEF2C, are responsible for an autosomal dominant form of intellectual disability (MRD20, also referred to as chromosome 5q14.3 deletion syndrome; OMIM 613443), a disorder in which a subset of cases present with stereotypic/repetitive movements and autistic features (Zweier et al., 2010; Paciorkowski et al., 2013). Sequencing of balanced chromosomal abnormalities (BCAs) in 273 subjects with a spectrum of congenital anomalies identified BCA breakpoints in eight subjects that altered a single topologically associated domain (TAD) encompassing the MEF2C gene that reached genome-wide significance (P=8.0E-09); decreased MEF2C expression was observed in four subjects for whom RNA from LCLs was available (Redin et al., 2016). Conditional knockout of MEF2C in the cortical neurons of mice resulted in reduced cortical network activity, due in part to increased inhibitory and decreased excitatory synaptic transmission, as well as the onset of behaviors related to autism, intellectual disability, and schizophrenia (Harrington et al., 2016).

Reports Added
[Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c...2019]
10/1/2018
4S
icon
4S

Decreased from 4S to 4S

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay. Heterozygous mutations in MEF2C, as well as heterozygous 5q14.3 deletions involving MEF2C, are responsible for an autosomal dominant form of intellectual disability (MRD20, also referred to as chromosome 5q14.3 deletion syndrome; OMIM 613443), a disorder in which a subset of cases present with stereotypic/repetitive movements and autistic features (Zweier et al., 2010; Paciorkowski et al., 2013). Sequencing of balanced chromosomal abnormalities (BCAs) in 273 subjects with a spectrum of congenital anomalies identified BCA breakpoints in eight subjects that altered a single topologically associated domain (TAD) encompassing the MEF2C gene that reached genome-wide significance (P=8.0E-09); decreased MEF2C expression was observed in four subjects for whom RNA from LCLs was available (Redin et al., 2016). Conditional knockout of MEF2C in the cortical neurons of mice resulted in reduced cortical network activity, due in part to increased inhibitory and decreased excitatory synaptic transmission, as well as the onset of behaviors related to autism, intellectual disability, and schizophrenia (Harrington et al., 2016).

Reports Added
[Novel MEF2C point mutations in Chinese patients with Rett (-like) syndrome or non-syndromic intellectual disability: insights into genotype-phenoty...2018] [Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
10/1/2017
4S
icon
4S

Decreased from 4S to 4S

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay. Heterozygous mutations in MEF2C, as well as heterozygous 5q14.3 deletions involving MEF2C, are responsible for an autosomal dominant form of intellectual disability (MRD20, also referred to as chromosome 5q14.3 deletion syndrome; OMIM 613443), a disorder in which a subset of cases present with stereotypic/repetitive movements and autistic features (Zweier et al., 2010; Paciorkowski et al., 2013). Sequencing of balanced chromosomal abnormalities (BCAs) in 273 subjects with a spectrum of congenital anomalies identified BCA breakpoints in eight subjects that altered a single topologically associated domain (TAD) encompassing the MEF2C gene that reached genome-wide significance (P=8.0E-09); decreased MEF2C expression was observed in four subjects for whom RNA from LCLs was available (Redin et al., 2016). Conditional knockout of MEF2C in the cortical neurons of mice resulted in reduced cortical network activity, due in part to increased inhibitory and decreased excitatory synaptic transmission, as well as the onset of behaviors related to autism, intellectual disability, and schizophrenia (Harrington et al., 2016).

Reports Added
[High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.2017]
7/1/2017
4S
icon
4S

Decreased from 4S to 4S

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay. Heterozygous mutations in MEF2C, as well as heterozygous 5q14.3 deletions involving MEF2C, are responsible for an autosomal dominant form of intellectual disability (MRD20, also referred to as chromosome 5q14.3 deletion syndrome; OMIM 613443), a disorder in which a subset of cases present with stereotypic/repetitive movements and autistic features (Zweier et al., 2010; Paciorkowski et al., 2013). Sequencing of balanced chromosomal abnormalities (BCAs) in 273 subjects with a spectrum of congenital anomalies identified BCA breakpoints in eight subjects that altered a single topologically associated domain (TAD) encompassing the MEF2C gene that reached genome-wide significance (P=8.0E-09); decreased MEF2C expression was observed in four subjects for whom RNA from LCLs was available (Redin et al., 2016). Conditional knockout of MEF2C in the cortical neurons of mice resulted in reduced cortical network activity, due in part to increased inhibitory and decreased excitatory synaptic transmission, as well as the onset of behaviors related to autism, intellectual disability, and schizophrenia (Harrington et al., 2016).

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
4/1/2017
4S
icon
4S

Decreased from 4S to 4S

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay. Heterozygous mutations in MEF2C, as well as heterozygous 5q14.3 deletions involving MEF2C, are responsible for an autosomal dominant form of intellectual disability (MRD20, also referred to as chromosome 5q14.3 deletion syndrome; OMIM 613443), a disorder in which a subset of cases present with stereotypic/repetitive movements and autistic features (Zweier et al., 2010; Paciorkowski et al., 2013). Sequencing of balanced chromosomal abnormalities (BCAs) in 273 subjects with a spectrum of congenital anomalies identified BCA breakpoints in eight subjects that altered a single topologically associated domain (TAD) encompassing the MEF2C gene that reached genome-wide significance (P=8.0E-09); decreased MEF2C expression was observed in four subjects for whom RNA from LCLs was available (Redin et al., 2016). Conditional knockout of MEF2C in the cortical neurons of mice resulted in reduced cortical network activity, due in part to increased inhibitory and decreased excitatory synaptic transmission, as well as the onset of behaviors related to autism, intellectual disability, and schizophrenia (Harrington et al., 2016).

Reports Added
[Refining the phenotype associated with MEF2C haploinsufficiency.2010] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Refining analyses of copy number variation identifies specific genes associated with developmental delay.2014] [Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental...2011] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 ...2010] [Refining the phenotype associated with MEF2C point mutations.2012] [Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation.1997] [Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C.1997] [Regulation of progenitor cell proliferation and granulocyte function by microRNA-223.2008] [Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo.2008] [Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection.2008] [Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2.2010] [Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95.2012] [MEF2C haploinsufficiency syndrome: Report of a new MEF2C mutation and review.2016] [Genome-wide characteristics of de novo mutations in autism2016] [Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c.2016] [Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders.2016] [MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways.2013] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016] [Experience-Dependent and Differential Regulation of Local and Long-Range Excitatory Neocortical Circuits by Postsynaptic Mef2c.2016] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
1/1/2017
4S
icon
4S

Decreased from 4S to 4S

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay. Heterozygous mutations in MEF2C, as well as heterozygous 5q14.3 deletions involving MEF2C, are responsible for an autosomal dominant form of intellectual disability (MRD20, also referred to as chromosome 5q14.3 deletion syndrome; OMIM 613443), a disorder in which a subset of cases present with stereotypic/repetitive movements and autistic features (Zweier et al., 2010; Paciorkowski et al., 2013). Sequencing of balanced chromosomal abnormalities (BCAs) in 273 subjects with a spectrum of congenital anomalies identified BCA breakpoints in eight subjects that altered a single topologically associated domain (TAD) encompassing the MEF2C gene that reached genome-wide significance (P=8.0E-09); decreased MEF2C expression was observed in four subjects for whom RNA from LCLs was available (Redin et al., 2016). Conditional knockout of MEF2C in the cortical neurons of mice resulted in reduced cortical network activity, due in part to increased inhibitory and decreased excitatory synaptic transmission, as well as the onset of behaviors related to autism, intellectual disability, and schizophrenia (Harrington et al., 2016).

Reports Added
[Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016] [Experience-Dependent and Differential Regulation of Local and Long-Range Excitatory Neocortical Circuits by Postsynaptic Mef2c.2016]
10/1/2016
4
icon
4S

Decreased from 4 to 4S

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay. Heterozygous mutations in MEF2C, as well as heterozygous 5q14.3 deletions involving MEF2C, are responsible for an autosomal dominant form of intellectual disability (MRD20, also referred to as chromosome 5q14.3 deletion syndrome; OMIM 613443), a disorder in which a subset of cases present with stereotypic/repetitive movements and autistic features (Zweier et al., 2010; Paciorkowski et al., 2013). Sequencing of balanced chromosomal abnormalities (BCAs) in 273 subjects with a spectrum of congenital anomalies identified BCA breakpoints in eight subjects that altered a single topologically associated domain (TAD) encompassing the MEF2C gene that reached genome-wide significance (P=8.0E-09); decreased MEF2C expression was observed in four subjects for whom RNA from LCLs was available (Redin et al., 2016). Conditional knockout of MEF2C in the cortical neurons of mice resulted in reduced cortical network activity, due in part to increased inhibitory and decreased excitatory synaptic transmission, as well as the onset of behaviors related to autism, intellectual disability, and schizophrenia (Harrington et al., 2016).

Reports Added
[Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders.2016] [MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways.2013] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
7/1/2016
4
icon
4

Decreased from 4 to 4

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay.

Reports Added
[MEF2C haploinsufficiency syndrome: Report of a new MEF2C mutation and review.2016] [Genome-wide characteristics of de novo mutations in autism2016] [Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c.2016]
1/1/2015
4
icon
4

Decreased from 4 to 4

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay.

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
10/1/2014
4
icon
4

Decreased from 4 to 4

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay.

Reports Added
[Refining analyses of copy number variation identifies specific genes associated with developmental delay.2014]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Rare variants in the MEF2C gene have been identified with autism (Novara et al., 2010; Neale et al., 2012) as well as with mental retardation and developmental delay.

Krishnan Probability Score

Score 0.60971710868985

Ranking 248/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.0042461741841837

Ranking 10718/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.78070824788947

Ranking 1911/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 6

Ranking 261/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.53238825041296

Ranking 326/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
MEF2B Myocyte-specific enhancer factor 2B Human Protein Binding 100271849 Q02080
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