MEF2C-Related Disorder

Mendelian MONDO:0013266 Pathograph 12 Show in embeddings browser Neurodevelopmental Disorder

MEF2C-related disorder is an autosomal dominant neurodevelopmental disorder with developmental delay, intellectual disability, severe speech impairment, hypotonia, seizures, and stereotypic movements. Loss of functional MEF2C can follow coding variants or deletions involving the gene. A separate group of structural variants leaves MEF2C coding sequence intact but disrupts its upstream regulatory domain, including the MEF2C-AS1 long noncoding RNA. These regulatory cases support reduced MEF2C expression, while the relative contributions of enhancer disconnection and lncRNA disruption remain incompletely resolved. Large multigene deletions can add effects from other genes and are not assumed to produce a purely MEF2C-mediated phenotype.

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1
Inheritance
9
Pathophys.
16
Phenotypes
12
Pathograph
1
Genes
2
Variants
4
Medical Actions
2
Subtypes
1
References
👪

Inheritance

1
Autosomal dominant HP:0000006
Most tested families have a de novo pathogenic variant. Rare transmission from an affected heterozygous parent or an unaffected mosaic parent has been reported.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:39666846 SUPPORT Other
"MEF2C-related disorder is an autosomal dominant disorder."
Establishes the inheritance pattern.
PMID:39666846 SUPPORT Other
"Rarely, a proband diagnosed with MEF2C-related disorder has the disorder as the result of a pathogenic variant inherited from an affected heterozygous parent or an unaffected mosaic parent."
Qualifies the predominantly de novo presentation.
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Subtypes

2
Coding loss of function
MEF2C hgnc:6996 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MEF2C (hgnc:6996). hgnc:6996 is a gene from the HUGO Gene Nomenclature Committee.
Pathogenic coding variants or deletions that directly impair MEF2C function.
Show evidence (1 reference)
PMID:32418612 SUPPORT In Vitro
"We showed that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding."
Patient-associated coding variants were tested for impaired DNA binding.
Regulatory structural variant
MEF2C hgnc:6996 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MEF2C (hgnc:6996). hgnc:6996 is a gene from the HUGO Gene Nomenclature Committee.
Rearrangements in the upstream MEF2C regulatory landscape with intact MEF2C coding sequence. DGAP191 and DGAP218 also disrupt MEF2C-AS1; enhancer and lncRNA mechanisms may both contribute.
Show evidence (2 references)
PMID:30445463 SUPPORT Human Clinical
"Structural variants (SVs) upstream of MEF2C, which do not disrupt the gene itself, have also been found in patients with a similar phenotype, suggesting that disruption of MEF2C regulatory elements can also cause a Rett-like phenotype."
Defines the intact-target regulatory disease context.
PMID:39060644 SUPPORT Human Clinical
"In both cases, the 5q14.3 breakpoints directly disrupt the lncRNA MEF2C-AS1."
The two exemplar alleles also physically disrupt a noncoding RNA gene.
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Pathophysiology

9
MEF2C Coding Loss of Function
Coding mutations can diminish MEF2C DNA-binding activity or remove functional gene sequence. The tested MADS-domain variants impair DNA binding without detectable interference with wild-type MEF2C in the reported assay, supporting loss of function.
Genetic context MEF2C hgnc:6996 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns MEF2C (hgnc:6996). hgnc:6996 is a gene from the HUGO Gene Nomenclature Committee. Genomic context: coding sequence allele_type: MEF2C loss-of-function coding variants or deletions variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Reduced Functional MEF2C Dosage Loss of one functional allele reduces the available MEF2C transcription-factor activity.
Show evidence (1 reference)
PMID:32418612 SUPPORT In Vitro
"We showed that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding."
Functional assays establish impaired DNA binding for tested coding variants.
MEF2C-AS1 Translocation Breakpoint (DGAP191)
A de novo translocation between chromosomes 5 and 7 interrupts MEF2C-AS1 at 5q14.3. The chromosome 7 break also overlaps a second lncRNA, ENSG00000285090. No protein-coding gene is directly disrupted in the 2024 reannotation.
Genetic context MEF2C-AS1 hgnc:48908 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns MEF2C-AS1 (hgnc:48908). hgnc:48908 is a gene from the HUGO Gene Nomenclature Committee. Variant type: translocation allele_type: DGAP191 de novo translocation with intact MEF2C coding sequence variant_origin: GERMLINE zygosity: HETEROZYGOUS
Affected regions (reference genome)
MEF2C-AS1 breakpoint region at 5q14.3 5q14.3
Within gene: MEF2C-AS1 hgnc:48908
The named region is the 5q14.3 breakpoint interval within the genomic span of MEF2C-AS1. It lies in the distal regulatory landscape of MEF2C. It does not denote the entire rearrangement, a deleted enhancer, or a precisely localized TAD boundary.
Upstream MEF2C neuronal regulatory domain 5q14.3
The upstream regulatory landscape contains multiple experimentally tested neuronal enhancers contacted by the MEF2C promoter. Rearrangements can alter its continuity while leaving MEF2C coding sequence intact; different alleles affect different parts of the domain.
Downstream
Altered Distal MEF2C Enhancer Connections The rearrangement separates MEF2C from distal regulatory elements; its exact neural contact effects have not been measured in the patient.
Impaired MEF2C-AS1 Regulatory Activity Interruption of the lncRNA locus may impair its support of neighboring MEF2C expression.
Show evidence (2 references)
PMID:39060644 SUPPORT Human Clinical
"In both cases, the 5q14.3 breakpoints directly disrupt the lncRNA MEF2C-AS1."
Localizes the 5q14.3 break within MEF2C-AS1, independently of the proposed expression mechanism.
PMID:39060644 SUPPORT Human Clinical
"In DGAP191, the 7q21.3 breakpoints additionally overlap the lncRNA ENSG00000285090, but no protein-coding genes are directly disrupted"
Defines physical overlap for this individual rearrangement.
MEF2C-AS1 Inversion Breakpoint (DGAP218)
A de novo chromosome 5 inversion has a q14.3 breakpoint within MEF2C-AS1 and a second breakpoint at 5p14.2. MEF2C-AS1 is the only gene directly interrupted at a breakpoint in the 2024 reannotation. MEF2C coding sequence remains intact.
Genetic context MEF2C-AS1 hgnc:48908 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns MEF2C-AS1 (hgnc:48908). hgnc:48908 is a gene from the HUGO Gene Nomenclature Committee. Variant type: inversion allele_type: DGAP218 de novo inversion with intact MEF2C coding sequence variant_origin: GERMLINE zygosity: HETEROZYGOUS
Affected regions (reference genome)
MEF2C-AS1 breakpoint region at 5q14.3 5q14.3
Within gene: MEF2C-AS1 hgnc:48908
The named region is the 5q14.3 breakpoint interval within the genomic span of MEF2C-AS1. It lies in the distal regulatory landscape of MEF2C. It does not denote the entire rearrangement, a deleted enhancer, or a precisely localized TAD boundary.
Upstream MEF2C neuronal regulatory domain 5q14.3
The upstream regulatory landscape contains multiple experimentally tested neuronal enhancers contacted by the MEF2C promoter. Rearrangements can alter its continuity while leaving MEF2C coding sequence intact; different alleles affect different parts of the domain.
Downstream
Altered Distal MEF2C Enhancer Connections The rearrangement separates MEF2C from distal regulatory elements; its exact neural contact effects have not been measured in the patient.
Impaired MEF2C-AS1 Regulatory Activity Interruption of the lncRNA locus may impair its support of neighboring MEF2C expression.
Show evidence (2 references)
PMID:39060644 SUPPORT Human Clinical
"In both cases, the 5q14.3 breakpoints directly disrupt the lncRNA MEF2C-AS1."
Localizes the 5q14.3 break within MEF2C-AS1, independently of the proposed expression mechanism.
PMID:39060644 SUPPORT Human Clinical
"In DGAP218, MEF2C-AS1 is the only gene of any class that is directly disrupted"
Defines physical overlap for this individual rearrangement.
Altered Distal MEF2C Enhancer Connections
Mechanism confidence: Hypothetical
The upstream MEF2C domain contains multiple distal regulatory elements that contact the promoter in SH-SY5Y cells. Reporter assays and zebrafish embryos demonstrate activity of individual elements. Rearrangements are proposed to impair the relevant connections, but these experiments do not recreate the complete DGAP191 or DGAP218 allele in developing human brain.
Downstream
Reduced MEF2C RNA Abundance Loss of effective distal enhancer connections is one proposed cause of reduced MEF2C expression.
Show evidence (2 references)
PMID:30445463 SUPPORT INDIRECT In Vitro
"Through circularized chromosome conformation capture sequencing (4C-seq) and the assay for transposase-accessible chromatin using sequencing (ATAC-seq), we revealed a complex interaction network in which the MEF2C promoter physically contacts several distal enhancers that are deleted or..."
4C and accessibility data identify the reference regulatory network and its relationship to reported SVs.
PMID:30445463 SUPPORT INDIRECT Model Organism
"Further analyses of their in vivo activity in zebrafish showed that each of these enhancers has a distinct activity pattern during development, with eight enhancers displaying neuronal activity."
Supports developmental enhancer activity; these are reporter assays of separate elements.
Impaired MEF2C-AS1 Regulatory Activity
Mechanism confidence: Hypothetical
MEF2C-AS1 overlaps the regulatory landscape and may support expression of MEF2C through its RNA product, the act of transcription, or both. siRNA knockdown in Lenti-X 293T cells lowers MEF2C RNA, supporting an RNA-dependent contribution. The assay does not establish the lncRNA mechanism in patient neural tissue or exclude enhancer disconnection.
MEF2C-AS1 hgnc:48908 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MEF2C-AS1 (hgnc:48908). hgnc:48908 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Reduced MEF2C RNA Abundance Reduced MEF2C-AS1 activity may contribute to the lower MEF2C abundance seen in rearrangement carriers.
Show evidence (1 reference)
PMID:39060644 SUPPORT INDIRECT In Vitro
"Furthermore, we experimentally tested the lncRNAs TBX2-AS1 and MEF2C-AS1 and found that knockdown of these lncRNAs resulted in decreased expression of the neighboring transcription factors TBX2 and MEF2C, respectively."
Perturbing lncRNA abundance supports regulation of the neighboring gene in cultured cells.
Reduced MEF2C RNA Abundance
Lymphoblastoid cell lines from DGAP131, DGAP191, DGAP218 and DGAP222 show reduced MEF2C RNA relative to controls. This is direct evidence of an expression consequence in LCLs. Its magnitude and cellular distribution during brain development remain unmeasured; neither global nor modular loss-of-expression is assigned from a single assayed cell type.
MEF2C hgnc:6996 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MEF2C (hgnc:6996). hgnc:6996 is a gene from the HUGO Gene Nomenclature Committee.
gene expression GO:0010467 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased gene expression (GO:0010467). GO:0010467 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Functional MEF2C Dosage Reduced expression is proposed to limit MEF2C activity during neural development; patient LCL measurements alone do not establish that tissue-specific step.
Show evidence (1 reference)
PMID:27841880 SUPPORT In Vitro
"Correspondingly, in four subjects that harbored BCA breakpoints up to 860 kb distal to MEF2C, and for which RNA from lymphoblastoid cell lines (LCLs) was available, MEF2C expression was significantly reduced compared to controls"
Measures the expression consequence in four patient-derived LCLs.
Reduced Functional MEF2C Dosage
Reduced MEF2C transcription-factor activity is the central coding haploinsufficiency mechanism. The regulatory-SV route is proposed to converge here through reduced expression, while MEF2C coding sequence remains intact. The neural consequences of the full regulatory alleles have not been directly assayed.
MEF2C hgnc:6996 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MEF2C (hgnc:6996). hgnc:6996 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Cortical Transcriptional Dysregulation Loss of functional MEF2C changes expression of cortical neuronal and microglial gene programs in mouse models.
Impaired Cortical Excitatory Synaptic Transmission Mef2c heterozygosity impairs cortical excitatory transmission in the mouse model.
Show evidence (1 reference)
PMID:32418612 SUPPORT In Vitro
"We showed that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding."
Coding-variant assays establish reduced activity of the transcription factor.
Cortical Transcriptional Dysregulation
Mef2c heterozygous mice show dysregulation of cortical genes enriched for excitatory-neuron and autism-associated functions, together with altered microglial gene expression. These model results support a multicellular developmental mechanism; they do not identify a single transcriptional intermediate for every human feature.
glutamatergic neuron CL:0000679 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glutamatergic neuron (CL:0000679). CL:0000679 is a cell type from the Cell Ontology. microglial cell CL:0000129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves microglial cell (CL:0000129). CL:0000129 is a cell type from the Cell Ontology.
regulation of DNA-templated transcription GO:0006355 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of DNA-templated transcription (GO:0006355). GO:0006355 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Show evidence (1 reference)
PMID:32418612 SUPPORT Model Organism
"We detected hundreds of dysregulated genes in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes."
Demonstrates altered cortical transcription in the heterozygous mouse model.
Impaired Cortical Excitatory Synaptic Transmission
Electrophysiology in Mef2c heterozygous mice shows deficits in cortical excitatory transmission. Conditional heterozygosity in excitatory neurons reproduces a subset of behaviors, while microglial heterozygosity reproduces social and repetitive behaviors, so the disease is not assigned exclusively to one cell type.
glutamatergic neuron CL:0000679 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glutamatergic neuron (CL:0000679). CL:0000679 is a cell type from the Cell Ontology.
chemical synaptic transmission GO:0007268 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased chemical synaptic transmission (GO:0007268). GO:0007268 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (2 references)
PMID:32418612 SUPPORT Model Organism
"DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) displayed numerous MCHS-related behaviors, including autism-related behaviors, changes in cortical gene expression, and deficits in cortical excitatory synaptic transmission."
The genetic mouse model provides electrophysiological evidence for this cellular defect.
PMID:32418612 SUPPORT Model Organism
"conditional Mef2c heterozygosity in forebrain excitatory neurons reproduced a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduced social deficits and repetitive behavior."
Preserves the separate contribution of neuronal and neuroimmune populations.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for MEF2C-Related Disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

16
Cardiovascular 1
Cardiovascular manifestations Abnormality of the cardiovascular system HP:0001626 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the cardiovascular system (HP:0001626). HP:0001626 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"MEF2C-related disorder is characterized by moderate-to-profound developmental delay with subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral manifestations (autistic features, sleep issues, stereotypic movements particularly of the hands), vision issues,..."
The cited GeneReviews summary reports cardiac manifestations without specifying a lesion.
Digestive 1
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35416405 SUPPORT Human Clinical
"The parents also noted their child had issues with chewing and swallowing, and therefore preferred soft or pureed foods."
Documents oral feeding difficulties in the parent survey.
Eye 2
Visual impairment HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual impairment (HP:0000505). HP:0000505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"MEF2C-related disorder is characterized by moderate-to-profound developmental delay with subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral manifestations (autistic features, sleep issues, stereotypic movements particularly of the hands), vision issues,..."
GeneReviews includes visual impairment in the clinical baseline.
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"treatment of refractive errors and strabismus per ophthalmologist"
The GeneReviews management summary identifies strabismus as a manifestation requiring care.
Head and Neck 1
Facial dysmorphism Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"MEF2C-related disorder is characterized by moderate-to-profound developmental delay with subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral manifestations (autistic features, sleep issues, stereotypic movements particularly of the hands), vision issues,..."
GeneReviews includes facial dysmorphism in the clinical baseline.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"MEF2C-related disorder is characterized by moderate-to-profound developmental delay with subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral manifestations (autistic features, sleep issues, stereotypic movements particularly of the hands), vision issues,..."
GeneReviews includes hypotonia in the clinical baseline.
Nervous System 10
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"MEF2C-related disorder is characterized by moderate-to-profound developmental delay with subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral manifestations (autistic features, sleep issues, stereotypic movements particularly of the hands), vision issues,..."
GeneReviews includes global developmental delay in the clinical baseline.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"MEF2C-related disorder is characterized by moderate-to-profound developmental delay with subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral manifestations (autistic features, sleep issues, stereotypic movements particularly of the hands), vision issues,..."
GeneReviews includes intellectual disability in the clinical baseline.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"MEF2C-related disorder is characterized by moderate-to-profound developmental delay with subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral manifestations (autistic features, sleep issues, stereotypic movements particularly of the hands), vision issues,..."
GeneReviews includes seizures in the clinical baseline.
Autistic features Autistic behavior HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"MEF2C-related disorder is characterized by moderate-to-profound developmental delay with subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral manifestations (autistic features, sleep issues, stereotypic movements particularly of the hands), vision issues,..."
GeneReviews includes autistic features in the clinical baseline.
Stereotypic movements Motor stereotypy HP:0000733 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor stereotypy (HP:0000733). HP:0000733 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"MEF2C-related disorder is characterized by moderate-to-profound developmental delay with subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral manifestations (autistic features, sleep issues, stereotypic movements particularly of the hands), vision issues,..."
GeneReviews includes stereotypic movements in the clinical baseline.
Sleep disturbance HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"MEF2C-related disorder is characterized by moderate-to-profound developmental delay with subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral manifestations (autistic features, sleep issues, stereotypic movements particularly of the hands), vision issues,..."
GeneReviews includes sleep disturbance in the clinical baseline.
Absent speech HP:0001344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent speech (HP:0001344). HP:0001344 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35416405 SUPPORT Human Clinical
"When assessing children over 5 years of age, the majority (82.1%) lacked any spoken words."
The parent-reported cohort establishes absent speech in this specified age group.
Inability to walk HP:0002540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inability to walk (HP:0002540). HP:0002540 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35416405 SUPPORT Human Clinical
"17.4% were able to walk with support, and the remaining 42.0% were unable to walk"
The parent survey distinguishes supported ambulation from inability to walk.
Bruxism HP:0003763 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bruxism (HP:0003763). HP:0003763 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35416405 SUPPORT Human Clinical
"Limited speech (82.1%), seizures (86.3%), bruxism (87.7%), repetitive movements (94.5%), and high pain tolerance (79.5%) were some of the prominent features."
Supports bruxism as a frequent cohort finding.
Reduced pain sensitivity Impaired pain sensation HP:0007328 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired pain sensation (HP:0007328). HP:0007328 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35416405 SUPPORT Human Clinical
"Limited speech (82.1%), seizures (86.3%), bruxism (87.7%), repetitive movements (94.5%), and high pain tolerance (79.5%) were some of the prominent features."
Supports reduced pain sensitivity without requiring complete analgesia.
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Genetic Associations

1
MEF2C
Gene: MEF2C hgnc:6996 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MEF2C (hgnc:6996). hgnc:6996 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:39666846 SUPPORT Other
"The diagnosis of MEF2C-related disorder is established in a proband by identification of a heterozygous pathogenic variant in MEF2C by molecular genetic testing."
Establishes the gene-disease association.
PMID:30445463 SUPPORT Human Clinical
"Although, for these very large deletions, deletion of other genes probably contributes to the aberrant phenotype"
Preserves potential contributions from other deleted genes.
Variants (2)
DGAP191 translocation affecting MEF2C-AS1 and the MEF2C regulatory domain
Gene: MEF2C-AS1 hgnc:48908 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MEF2C-AS1 (hgnc:48908). hgnc:48908 is a gene from the HUGO Gene Nomenclature Committee. Regulatory target: MEF2C hgnc:6996 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant has a reported or proposed regulatory effect on this gene This variant has a reported or proposed regulatory effect on MEF2C (hgnc:6996). hgnc:6996 is a gene from the HUGO Gene Nomenclature Committee. translocation
Affected regions (reference genome)
MEF2C-AS1 breakpoint region at 5q14.3 5q14.3
Within gene: MEF2C-AS1 hgnc:48908
The named region is the 5q14.3 breakpoint interval within the genomic span of MEF2C-AS1. It lies in the distal regulatory landscape of MEF2C. It does not denote the entire rearrangement, a deleted enhancer, or a precisely localized TAD boundary.
Upstream MEF2C neuronal regulatory domain 5q14.3
The upstream regulatory landscape contains multiple experimentally tested neuronal enhancers contacted by the MEF2C promoter. Rearrangements can alter its continuity while leaving MEF2C coding sequence intact; different alleles affect different parts of the domain.
De novo t(5;7)(q14.3;q21.3). Andersen et al. Table 1 reports GRCh38/hg38 breakpoint intervals chr5:89411065-89411070 and chr7:94378248-94378255. These are the source-reported breakpoint intervals, not a single invented junction. The chr5 break lies within MEF2C-AS1; the chr7 break overlaps ENSG00000285090. MEF2C coding sequence is intact. The 2024 report reanalyzes the same individual studied by Redin et al., not a new independent allele.
Functional effects
MEF2C expression regulation
MEF2C RNA is reduced in patient LCLs. Enhancer disconnection and interruption of MEF2C-AS1 are both plausible contributors. MEF2C-AS1 knockdown lowers MEF2C in 293T cells, but does not recreate this patient rearrangement or demonstrate its effect in developing brain.
Mechanism: Distal regulatory-domain rearrangement with lncRNA interruption
Show evidence (4 references)
PMID:39060644 SUPPORT Human Clinical
"In both cases, the 5q14.3 breakpoints directly disrupt the lncRNA MEF2C-AS1."
The primary reanalysis links both named subjects to physical MEF2C-AS1 disruption.
PMID:39060644 SUPPORT Human Clinical
"We additionally identified two cases, DGAP191 and DGAP218, with chromosomal rearrangements that disrupt the lncRNA MEF2C-AS1. ... t(5;7)(5pter→5q14.3(+)(89,411,06{3–5})::7q21.3(+)(94,378,2{48–50})→7qter;7pter→7q21.3(+)(94,378,25{3–5})::5q14.3(+)(89,411,07{0–2})→5qter)dn"
The authors identify the two MEF2C-AS1-disrupting rearrangements in prose; the explicit ellipsis separates that statement from this case's derivative-sequence notation. The notation preserves the published junction detail, while Table 1 gives the summarized GRCh38 breakpoint intervals retained in the description.
PMID:27841880 SUPPORT In Vitro
"Correspondingly, in four subjects that harbored BCA breakpoints up to 860 kb distal to MEF2C, and for which RNA from lymphoblastoid cell lines (LCLs) was available, MEF2C expression was significantly reduced compared to controls"
Patient-derived LCLs establish an RNA abundance effect.
+ 1 more reference
DGAP218 inversion affecting MEF2C-AS1 and the MEF2C regulatory domain
Gene: MEF2C-AS1 hgnc:48908 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MEF2C-AS1 (hgnc:48908). hgnc:48908 is a gene from the HUGO Gene Nomenclature Committee. Regulatory target: MEF2C hgnc:6996 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant has a reported or proposed regulatory effect on this gene This variant has a reported or proposed regulatory effect on MEF2C (hgnc:6996). hgnc:6996 is a gene from the HUGO Gene Nomenclature Committee. inversion
Affected regions (reference genome)
MEF2C-AS1 breakpoint region at 5q14.3 5q14.3
Within gene: MEF2C-AS1 hgnc:48908
The named region is the 5q14.3 breakpoint interval within the genomic span of MEF2C-AS1. It lies in the distal regulatory landscape of MEF2C. It does not denote the entire rearrangement, a deleted enhancer, or a precisely localized TAD boundary.
Upstream MEF2C neuronal regulatory domain 5q14.3
The upstream regulatory landscape contains multiple experimentally tested neuronal enhancers contacted by the MEF2C promoter. Rearrangements can alter its continuity while leaving MEF2C coding sequence intact; different alleles affect different parts of the domain.
De novo chromosome 5 inversion. Andersen et al. Table 1 reports GRCh38/hg38 breakpoint intervals chr5:24272189-24272193 and chr5:89105026-89105031. Its sequence-based interpretation places the breakpoints at 5p14.2 and 5q14.3, although the historical karyotype was inv(5)(p12q13.1). The published derivative description includes a 15-bp junction insertion, TATTTATATGACAAG. MEF2C-AS1 is interrupted while MEF2C coding sequence remains intact. This is the same DGAP218 previously studied by Redin et al.
Functional effects
MEF2C expression regulation
MEF2C RNA is reduced in patient LCLs. Enhancer disconnection and interruption of MEF2C-AS1 are both plausible contributors. MEF2C-AS1 knockdown lowers MEF2C in 293T cells, but does not recreate this patient rearrangement or demonstrate its effect in developing brain.
Mechanism: Distal regulatory-domain rearrangement with lncRNA interruption
Show evidence (4 references)
PMID:39060644 SUPPORT Human Clinical
"In both cases, the 5q14.3 breakpoints directly disrupt the lncRNA MEF2C-AS1."
The primary reanalysis links both named subjects to physical MEF2C-AS1 disruption.
PMID:39060644 SUPPORT Human Clinical
"We additionally identified two cases, DGAP191 and DGAP218, with chromosomal rearrangements that disrupt the lncRNA MEF2C-AS1. ... inv(5)(pter→p14.2(+)(24,272,19{3})::q14.3(-)(89,105,02{6})→p14.2(-)(24,272,189)::TATTTATATGACAAG::q14.3(+)(89,105,031)→qter)dn"
The authors identify the two MEF2C-AS1-disrupting rearrangements in prose; the explicit ellipsis separates that statement from this case's derivative-sequence notation. The notation preserves the published junction detail, while Table 1 gives the summarized GRCh38 breakpoint intervals retained in the description.
PMID:27841880 SUPPORT In Vitro
"Correspondingly, in four subjects that harbored BCA breakpoints up to 860 kb distal to MEF2C, and for which RNA from lymphoblastoid cell lines (LCLs) was available, MEF2C expression was significantly reduced compared to controls"
Patient-derived LCLs establish an RNA abundance effect.
+ 1 more reference
💊

Medical Actions

4
Developmental and rehabilitation support
Developmental and educational services, physical and occupational therapy, and individualized communication support address functional needs.
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"Developmental and educational services; treatment of gait abnormalities per orthopedist, physical medicine and rehabilitation specialist, and/or physical or occupational therapist"
Supports multidisciplinary developmental and motor care.
Individualized seizure management
Seizures receive standard treatment tailored to seizure type and response; this entry does not assert a specific preferred drug for regulatory-SV disease.
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"standard treatment for gastroesophageal reflux disease, constipation, and seizures"
GeneReviews recommends standard symptomatic seizure management.
Feeding and gastrointestinal support
Assess oral feeding safety and nutritional needs, provide feeding support, and treat reflux or constipation when present.
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"feeding support as needed; standard treatment for gastroesophageal reflux disease, constipation, and seizures"
Supports feeding and gastrointestinal care.
Cardiac, visual, and infection-directed care
Cardiology and ophthalmology care are guided by individual findings. Recurrent respiratory or ear infections warrant standard treatment and hearing assessment when indicated.
Show evidence (2 references)
PMID:39666846 SUPPORT Other
"treatment of cardiac manifestations per cardiologist; treatment of refractive errors and strabismus per ophthalmologist"
Supports specialist care for documented cardiac and visual manifestations.
PMID:39666846 SUPPORT Other
"antibiotics as needed for recurrent respiratory infections and recurrent otitis media"
Supports treatment of recurrent infections as required.
🔬

Diagnosis

2
Molecular genetic diagnosis
Molecular testing identifies a heterozygous pathogenic MEF2C variant in the established coding/deletion disorder. Variant interpretation must fit the clinical findings.
Show evidence (1 reference)
PMID:39666846 SUPPORT Other
"The diagnosis of MEF2C-related disorder is established in a proband by identification of a heterozygous pathogenic variant in MEF2C by molecular genetic testing."
Provides the baseline diagnostic criterion.
Structural variant and breakpoint assessment
In a compatible phenotype with intact MEF2C coding sequence, assessment of balanced rearrangements and distal copy-number changes can identify a regulatory hypothesis. Breakpoint mapping, the other affected loci, and functional evidence matter; overlap with the domain alone does not establish a diagnosis.
Show evidence (2 references)
PMID:27841880 SUPPORT Human Clinical
"These data strongly argue for the implementation of technologies capable of detecting both balanced and unbalanced genomic rearrangements."
Supports structural-variant detection beyond sequence variants.
PMID:30445463 SUPPORT Human Clinical
"Structural variants (SVs) upstream of MEF2C, which do not disrupt the gene itself, have also been found in patients with a similar phenotype, suggesting that disruption of MEF2C regulatory elements can also cause a Rett-like phenotype."
Supports considering distal structural variants in the relevant phenotype.
{ }

Source YAML

click to show 
name: MEF2C-Related Disorder
creation_date: '2026-09-21T23:01:23Z'
category: Mendelian
synonyms:
- MEF2C haploinsufficiency syndrome
- MEF2C-related neurodevelopmental disorder
- MEF2C deficiency
- Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language
- NEDHSIL
description: >-
  MEF2C-related disorder is an autosomal dominant neurodevelopmental disorder with developmental
  delay, intellectual disability, severe speech impairment, hypotonia, seizures, and stereotypic
  movements. Loss of functional MEF2C can follow coding variants or deletions involving the
  gene. A separate group of structural variants leaves MEF2C coding sequence intact but disrupts
  its upstream regulatory domain, including the MEF2C-AS1 long noncoding RNA. These regulatory
  cases support reduced MEF2C expression, while the relative contributions of enhancer disconnection
  and lncRNA disruption remain incompletely resolved. Large multigene deletions can add effects
  from other genes and are not assumed to produce a purely MEF2C-mediated phenotype.
disease_term:
  preferred_term: MEF2C-related disorder
  term:
    id: MONDO:0013266
    label: neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language
parents:
- Neurodevelopmental Disorder
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Most tested families have a de novo pathogenic variant. Rare transmission from an affected
    heterozygous parent or an unaffected mosaic parent has been reported.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: MEF2C-related disorder is an autosomal dominant disorder.
    explanation: Establishes the inheritance pattern.
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rarely, a proband diagnosed with MEF2C-related disorder has the disorder as the result
      of a pathogenic variant inherited from an affected heterozygous parent or an unaffected
      mosaic parent.
    explanation: Qualifies the predominantly de novo presentation.
has_subtypes:
- name: Coding loss of function
  description: Pathogenic coding variants or deletions that directly impair MEF2C function.
  genes:
  - preferred_term: MEF2C
    term:
      id: hgnc:6996
      label: MEF2C
  evidence:
  - reference: PMID:32418612
    reference_title: MEF2C Hypofunction in Neuronal and Neuroimmune Populations Produces MEF2C Haploinsufficiency Syndrome-like Behaviors in Mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We showed that MCHS-associated missense mutations cluster in the conserved DNA binding
      domain and disrupt MEF2C DNA binding.
    explanation: Patient-associated coding variants were tested for impaired DNA binding.
- name: Regulatory structural variant
  description: >-
    Rearrangements in the upstream MEF2C regulatory landscape with intact MEF2C coding sequence.
    DGAP191 and DGAP218 also disrupt MEF2C-AS1; enhancer and lncRNA mechanisms may both contribute.
  genes:
  - preferred_term: MEF2C
    term:
      id: hgnc:6996
      label: MEF2C
  evidence:
  - reference: PMID:30445463
    reference_title: A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett-like characteristics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Structural variants (SVs) upstream of MEF2C, which do not disrupt the gene itself, have
      also been found in patients with a similar phenotype, suggesting that disruption of MEF2C
      regulatory elements can also cause a Rett-like phenotype.
    explanation: Defines the intact-target regulatory disease context.
  - reference: PMID:39060644
    reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In both cases, the 5q14.3 breakpoints directly disrupt the lncRNA MEF2C-AS1.
    explanation: The two exemplar alleles also physically disrupt a noncoding RNA gene.
pathophysiology:
- name: MEF2C Coding Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  subtypes:
  - Coding loss of function
  genetic_context:
    gene:
      preferred_term: MEF2C
      term:
        id: hgnc:6996
        label: MEF2C
    allele_type: MEF2C loss-of-function coding variants or deletions
    genomic_contexts:
    - coding sequence
    zygosity: HETEROZYGOUS
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  description: >-
    Coding mutations can diminish MEF2C DNA-binding activity or remove functional gene sequence.
    The tested MADS-domain variants impair DNA binding without detectable interference with
    wild-type MEF2C in the reported assay, supporting loss of function.
  evidence:
  - reference: PMID:32418612
    reference_title: MEF2C Hypofunction in Neuronal and Neuroimmune Populations Produces MEF2C Haploinsufficiency Syndrome-like Behaviors in Mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We showed that MCHS-associated missense mutations cluster in the conserved DNA binding
      domain and disrupt MEF2C DNA binding.
    explanation: Functional assays establish impaired DNA binding for tested coding variants.
  downstream:
  - target: Reduced Functional MEF2C Dosage
    description: Loss of one functional allele reduces the available MEF2C transcription-factor activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32418612
      reference_title: MEF2C Hypofunction in Neuronal and Neuroimmune Populations Produces MEF2C Haploinsufficiency Syndrome-like Behaviors in Mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In a MEF2 response element DNA binding assay, all five of the MADS domain patient mutations
        caused a loss of MEF2C DNA binding
      explanation: Demonstrates the coding mechanism leading to reduced functional activity.
- name: MEF2C-AS1 Translocation Breakpoint (DGAP191)
  biological_scale: MOLECULAR
  role: trigger
  subtypes:
  - Regulatory structural variant
  genetic_context:
    gene:
      preferred_term: MEF2C-AS1
      term:
        id: hgnc:48908
        label: MEF2C-AS1
    variant_type: translocation
    zygosity: HETEROZYGOUS
    variant_origin: GERMLINE
    allele_type: DGAP191 de novo translocation with intact MEF2C coding sequence
    affected_regions:
    - name: MEF2C-AS1 breakpoint region at 5q14.3
      chromosomal_region: 5q14.3
      within_gene:
        preferred_term: MEF2C-AS1
        term:
          id: hgnc:48908
          label: MEF2C-AS1
      description: >-
        The named region is the 5q14.3 breakpoint interval within the genomic span of MEF2C-AS1.
        It lies in the distal regulatory landscape of MEF2C. It does not denote the entire rearrangement,
        a deleted enhancer, or a precisely localized TAD boundary.
    - name: Upstream MEF2C neuronal regulatory domain
      chromosomal_region: 5q14.3
      description: >-
        The upstream regulatory landscape contains multiple experimentally tested neuronal enhancers
        contacted by the MEF2C promoter. Rearrangements can alter its continuity while leaving
        MEF2C coding sequence intact; different alleles affect different parts of the domain.
  description: >-
    A de novo translocation between chromosomes 5 and 7 interrupts MEF2C-AS1 at 5q14.3. The
    chromosome 7 break also overlaps a second lncRNA, ENSG00000285090. No protein-coding gene
    is directly disrupted in the 2024 reannotation.
  evidence:
  - reference: PMID:39060644
    reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In both cases, the 5q14.3 breakpoints directly disrupt the lncRNA MEF2C-AS1.
    explanation: >-
      Localizes the 5q14.3 break within MEF2C-AS1, independently of the proposed expression
      mechanism.
  - reference: PMID:39060644
    reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In DGAP191, the 7q21.3 breakpoints additionally overlap the lncRNA ENSG00000285090, but
      no protein-coding genes are directly disrupted
    explanation: Defines physical overlap for this individual rearrangement.
  downstream:
  - target: Altered Distal MEF2C Enhancer Connections
    description: >-
      The rearrangement separates MEF2C from distal regulatory elements; its exact neural contact
      effects have not been measured in the patient.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39060644
      reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thus, the separation of these distal enhancers from MEF2C could certainly contribute
        to the phenotypes of these individuals.
      explanation: The authors retain enhancer separation as a candidate contribution in these two cases.
      directness: INDIRECT
  - target: Impaired MEF2C-AS1 Regulatory Activity
    description: Interruption of the lncRNA locus may impair its support of neighboring MEF2C expression.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39060644
      reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thus, for DGAP191 and DGAP218 we now propose that the disruption of MEF2C-AS1 leads
        to decreased expression of MEF2C, resulting in neurological phenotypes.
      explanation: This is the authors' mechanistic proposal, not proof of the full patient pathway.
      directness: INDIRECT
- name: MEF2C-AS1 Inversion Breakpoint (DGAP218)
  biological_scale: MOLECULAR
  role: trigger
  subtypes:
  - Regulatory structural variant
  genetic_context:
    gene:
      preferred_term: MEF2C-AS1
      term:
        id: hgnc:48908
        label: MEF2C-AS1
    variant_type: inversion
    zygosity: HETEROZYGOUS
    variant_origin: GERMLINE
    allele_type: DGAP218 de novo inversion with intact MEF2C coding sequence
    affected_regions:
    - name: MEF2C-AS1 breakpoint region at 5q14.3
      chromosomal_region: 5q14.3
      within_gene:
        preferred_term: MEF2C-AS1
        term:
          id: hgnc:48908
          label: MEF2C-AS1
      description: >-
        The named region is the 5q14.3 breakpoint interval within the genomic span of MEF2C-AS1.
        It lies in the distal regulatory landscape of MEF2C. It does not denote the entire rearrangement,
        a deleted enhancer, or a precisely localized TAD boundary.
    - name: Upstream MEF2C neuronal regulatory domain
      chromosomal_region: 5q14.3
      description: >-
        The upstream regulatory landscape contains multiple experimentally tested neuronal enhancers
        contacted by the MEF2C promoter. Rearrangements can alter its continuity while leaving
        MEF2C coding sequence intact; different alleles affect different parts of the domain.
  description: >-
    A de novo chromosome 5 inversion has a q14.3 breakpoint within MEF2C-AS1 and a second breakpoint
    at 5p14.2. MEF2C-AS1 is the only gene directly interrupted at a breakpoint in the 2024 reannotation.
    MEF2C coding sequence remains intact.
  evidence:
  - reference: PMID:39060644
    reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In both cases, the 5q14.3 breakpoints directly disrupt the lncRNA MEF2C-AS1.
    explanation: >-
      Localizes the 5q14.3 break within MEF2C-AS1, independently of the proposed expression
      mechanism.
  - reference: PMID:39060644
    reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In DGAP218, MEF2C-AS1 is the only gene of any class that is directly disrupted
    explanation: Defines physical overlap for this individual rearrangement.
  downstream:
  - target: Altered Distal MEF2C Enhancer Connections
    description: >-
      The rearrangement separates MEF2C from distal regulatory elements; its exact neural contact
      effects have not been measured in the patient.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39060644
      reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thus, the separation of these distal enhancers from MEF2C could certainly contribute
        to the phenotypes of these individuals.
      explanation: The authors retain enhancer separation as a candidate contribution in these two cases.
      directness: INDIRECT
  - target: Impaired MEF2C-AS1 Regulatory Activity
    description: Interruption of the lncRNA locus may impair its support of neighboring MEF2C expression.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39060644
      reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thus, for DGAP191 and DGAP218 we now propose that the disruption of MEF2C-AS1 leads
        to decreased expression of MEF2C, resulting in neurological phenotypes.
      explanation: This is the authors' mechanistic proposal, not proof of the full patient pathway.
      directness: INDIRECT
- name: Altered Distal MEF2C Enhancer Connections
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  subtypes:
  - Regulatory structural variant
  description: >-
    The upstream MEF2C domain contains multiple distal regulatory elements that contact the
    promoter in SH-SY5Y cells. Reporter assays and zebrafish embryos demonstrate activity of
    individual elements. Rearrangements are proposed to impair the relevant connections, but
    these experiments do not recreate the complete DGAP191 or DGAP218 allele in developing human
    brain.
  evidence:
  - reference: PMID:30445463
    reference_title: A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett-like characteristics.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Through circularized chromosome conformation capture sequencing (4C-seq) and the assay
      for transposase-accessible chromatin using sequencing (ATAC-seq), we revealed a complex
      interaction network in which the MEF2C promoter physically contacts several distal enhancers
      that are deleted or translocated by disease-associated SVs.
    explanation: >-
      4C and accessibility data identify the reference regulatory network and its relationship
      to reported SVs.
    directness: INDIRECT
  - reference: PMID:30445463
    reference_title: A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett-like characteristics.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Further analyses of their in vivo activity in zebrafish showed that each of these enhancers
      has a distinct activity pattern during development, with eight enhancers displaying neuronal
      activity.
    explanation: Supports developmental enhancer activity; these are reporter assays of separate elements.
    directness: INDIRECT
  downstream:
  - target: Reduced MEF2C RNA Abundance
    description: >-
      Loss of effective distal enhancer connections is one proposed cause of reduced MEF2C expression.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30445463
      reference_title: A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett-like characteristics.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The MEF2C promoter interacts with multiple distal neuronal enhancers in its upstream
        region and the disruption of these interactions by chromosomal abnormalities could lead
        to haploinsufficiency in early brain development and result in a similar phenotypic
        outcome as MEF2C coding mutations.
      explanation: >-
        The study proposes this chain from enhancer-network disruption to developmental MEF2C
        deficiency.
      directness: INDIRECT
- name: Impaired MEF2C-AS1 Regulatory Activity
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  subtypes:
  - Regulatory structural variant
  genes:
  - preferred_term: MEF2C-AS1
    term:
      id: hgnc:48908
      label: MEF2C-AS1
  description: >-
    MEF2C-AS1 overlaps the regulatory landscape and may support expression of MEF2C through
    its RNA product, the act of transcription, or both. siRNA knockdown in Lenti-X 293T cells
    lowers MEF2C RNA, supporting an RNA-dependent contribution. The assay does not establish
    the lncRNA mechanism in patient neural tissue or exclude enhancer disconnection.
  evidence:
  - reference: PMID:39060644
    reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, we experimentally tested the lncRNAs TBX2-AS1 and MEF2C-AS1 and found that
      knockdown of these lncRNAs resulted in decreased expression of the neighboring transcription
      factors TBX2 and MEF2C, respectively.
    explanation: Perturbing lncRNA abundance supports regulation of the neighboring gene in cultured cells.
    directness: INDIRECT
  downstream:
  - target: Reduced MEF2C RNA Abundance
    description: >-
      Reduced MEF2C-AS1 activity may contribute to the lower MEF2C abundance seen in rearrangement
      carriers.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39060644
      reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Furthermore, we experimentally tested the lncRNAs TBX2-AS1 and MEF2C-AS1 and found that
        knockdown of these lncRNAs resulted in decreased expression of the neighboring transcription
        factors TBX2 and MEF2C, respectively.
      explanation: >-
        The knockdown effect supports this candidate edge, with extrapolation to the patient
        rearrangements.
      directness: INDIRECT
- name: Reduced MEF2C RNA Abundance
  biological_scale: MOLECULAR
  subtypes:
  - Regulatory structural variant
  genes:
  - preferred_term: MEF2C
    term:
      id: hgnc:6996
      label: MEF2C
  description: >-
    Lymphoblastoid cell lines from DGAP131, DGAP191, DGAP218 and DGAP222 show reduced MEF2C
    RNA relative to controls. This is direct evidence of an expression consequence in LCLs.
    Its magnitude and cellular distribution during brain development remain unmeasured; neither
    global nor modular loss-of-expression is assigned from a single assayed cell type.
  biological_processes:
  - preferred_term: gene expression
    term:
      id: GO:0010467
      label: gene expression
    modifier: DECREASED
  evidence:
  - reference: PMID:27841880
    reference_title: The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Correspondingly, in four subjects that harbored BCA breakpoints up to 860 kb distal to
      MEF2C, and for which RNA from lymphoblastoid cell lines (LCLs) was available, MEF2C expression
      was significantly reduced compared to controls
    explanation: Measures the expression consequence in four patient-derived LCLs.
  downstream:
  - target: Reduced Functional MEF2C Dosage
    description: >-
      Reduced expression is proposed to limit MEF2C activity during neural development; patient
      LCL measurements alone do not establish that tissue-specific step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30445463
      reference_title: A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett-like characteristics.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The MEF2C promoter interacts with multiple distal neuronal enhancers in its upstream
        region and the disruption of these interactions by chromosomal abnormalities could lead
        to haploinsufficiency in early brain development and result in a similar phenotypic
        outcome as MEF2C coding mutations.
      explanation: >-
        Supports the proposed neural link while preserving the difference between regulatory
        mapping and patient brain measurements.
      directness: INDIRECT
- name: Reduced Functional MEF2C Dosage
  biological_scale: MOLECULAR
  genes:
  - preferred_term: MEF2C
    term:
      id: hgnc:6996
      label: MEF2C
  description: >-
    Reduced MEF2C transcription-factor activity is the central coding haploinsufficiency mechanism.
    The regulatory-SV route is proposed to converge here through reduced expression, while MEF2C
    coding sequence remains intact. The neural consequences of the full regulatory alleles have
    not been directly assayed.
  evidence:
  - reference: PMID:32418612
    reference_title: MEF2C Hypofunction in Neuronal and Neuroimmune Populations Produces MEF2C Haploinsufficiency Syndrome-like Behaviors in Mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We showed that MCHS-associated missense mutations cluster in the conserved DNA binding
      domain and disrupt MEF2C DNA binding.
    explanation: Coding-variant assays establish reduced activity of the transcription factor.
  downstream:
  - target: Cortical Transcriptional Dysregulation
    causal_link_type: DIRECT
    description: >-
      Loss of functional MEF2C changes expression of cortical neuronal and microglial gene programs
      in mouse models.
    evidence:
    - reference: PMID:32418612
      reference_title: MEF2C Hypofunction in Neuronal and Neuroimmune Populations Produces MEF2C Haploinsufficiency Syndrome-like Behaviors in Mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We detected hundreds of dysregulated genes in Mef2c-Het cortex, including significant
        enrichments of autism risk and excitatory neuron genes.
      explanation: Connects Mef2c hypofunction with cortical transcriptional changes.
  - target: Impaired Cortical Excitatory Synaptic Transmission
    description: Mef2c heterozygosity impairs cortical excitatory transmission in the mouse model.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32418612
      reference_title: MEF2C Hypofunction in Neuronal and Neuroimmune Populations Produces MEF2C Haploinsufficiency Syndrome-like Behaviors in Mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) displayed numerous
        MCHS-related behaviors, including autism-related behaviors, changes in cortical gene
        expression, and deficits in cortical excitatory synaptic transmission.
      explanation: >-
        The genetic perturbation directly establishes a synaptic consequence; the intermediate
        transcriptional targets are unresolved.
- name: Cortical Transcriptional Dysregulation
  biological_scale: MOLECULAR
  description: >-
    Mef2c heterozygous mice show dysregulation of cortical genes enriched for excitatory-neuron
    and autism-associated functions, together with altered microglial gene expression. These
    model results support a multicellular developmental mechanism; they do not identify a single
    transcriptional intermediate for every human feature.
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: regulation of DNA-templated transcription
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:32418612
    reference_title: MEF2C Hypofunction in Neuronal and Neuroimmune Populations Produces MEF2C Haploinsufficiency Syndrome-like Behaviors in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We detected hundreds of dysregulated genes in Mef2c-Het cortex, including significant
      enrichments of autism risk and excitatory neuron genes.
    explanation: Demonstrates altered cortical transcription in the heterozygous mouse model.
- name: Impaired Cortical Excitatory Synaptic Transmission
  biological_scale: CELLULAR
  description: >-
    Electrophysiology in Mef2c heterozygous mice shows deficits in cortical excitatory transmission.
    Conditional heterozygosity in excitatory neurons reproduces a subset of behaviors, while
    microglial heterozygosity reproduces social and repetitive behaviors, so the disease is
    not assigned exclusively to one cell type.
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: DECREASED
  evidence:
  - reference: PMID:32418612
    reference_title: MEF2C Hypofunction in Neuronal and Neuroimmune Populations Produces MEF2C Haploinsufficiency Syndrome-like Behaviors in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) displayed numerous MCHS-related
      behaviors, including autism-related behaviors, changes in cortical gene expression, and
      deficits in cortical excitatory synaptic transmission.
    explanation: The genetic mouse model provides electrophysiological evidence for this cellular defect.
  - reference: PMID:32418612
    reference_title: MEF2C Hypofunction in Neuronal and Neuroimmune Populations Produces MEF2C Haploinsufficiency Syndrome-like Behaviors in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      conditional Mef2c heterozygosity in forebrain excitatory neurons reproduced a subset of
      the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduced
      social deficits and repetitive behavior.
    explanation: Preserves the separate contribution of neuronal and neuroimmune populations.
phenotypes:
- name: Global developmental delay
  category: Neurological
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  description: Developmental delay affects speech and motor development and can be moderate to profound.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MEF2C-related disorder is characterized by moderate-to-profound developmental delay with
      subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral
      manifestations (autistic features, sleep issues, stereotypic movements particularly of
      the hands), vision issues, and cardiac manifestations.
    explanation: GeneReviews includes global developmental delay in the clinical baseline.
- name: Intellectual disability
  category: Neurological
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  description: Intellectual disability follows early developmental delay and is often severe.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MEF2C-related disorder is characterized by moderate-to-profound developmental delay with
      subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral
      manifestations (autistic features, sleep issues, stereotypic movements particularly of
      the hands), vision issues, and cardiac manifestations.
    explanation: GeneReviews includes intellectual disability in the clinical baseline.
- name: Hypotonia
  category: Neurological
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  description: Low muscle tone is a characteristic feature and contributes to motor difficulties.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MEF2C-related disorder is characterized by moderate-to-profound developmental delay with
      subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral
      manifestations (autistic features, sleep issues, stereotypic movements particularly of
      the hands), vision issues, and cardiac manifestations.
    explanation: GeneReviews includes hypotonia in the clinical baseline.
- name: Seizures
  category: Neurological
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  description: Epilepsy is common, with variable seizure types and severity.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MEF2C-related disorder is characterized by moderate-to-profound developmental delay with
      subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral
      manifestations (autistic features, sleep issues, stereotypic movements particularly of
      the hands), vision issues, and cardiac manifestations.
    explanation: GeneReviews includes seizures in the clinical baseline.
- name: Autistic features
  category: Neurological
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  description: >-
    Autistic features occur in the neurobehavioral spectrum; this does not assert a formal autism
    diagnosis in every individual.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MEF2C-related disorder is characterized by moderate-to-profound developmental delay with
      subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral
      manifestations (autistic features, sleep issues, stereotypic movements particularly of
      the hands), vision issues, and cardiac manifestations.
    explanation: GeneReviews includes autistic features in the clinical baseline.
- name: Stereotypic movements
  category: Neurological
  phenotype_term:
    preferred_term: Motor stereotypy
    term:
      id: HP:0000733
      label: Motor stereotypy
  description: Repetitive movements particularly involve the hands.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MEF2C-related disorder is characterized by moderate-to-profound developmental delay with
      subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral
      manifestations (autistic features, sleep issues, stereotypic movements particularly of
      the hands), vision issues, and cardiac manifestations.
    explanation: GeneReviews includes stereotypic movements in the clinical baseline.
- name: Sleep disturbance
  category: Neurological
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  description: Sleep initiation and maintenance difficulties are reported.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MEF2C-related disorder is characterized by moderate-to-profound developmental delay with
      subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral
      manifestations (autistic features, sleep issues, stereotypic movements particularly of
      the hands), vision issues, and cardiac manifestations.
    explanation: GeneReviews includes sleep disturbance in the clinical baseline.
- name: Facial dysmorphism
  category: Craniofacial
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  description: Dysmorphic facial features vary and are not a sufficient diagnostic gestalt.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MEF2C-related disorder is characterized by moderate-to-profound developmental delay with
      subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral
      manifestations (autistic features, sleep issues, stereotypic movements particularly of
      the hands), vision issues, and cardiac manifestations.
    explanation: GeneReviews includes facial dysmorphism in the clinical baseline.
- name: Visual impairment
  category: Ophthalmological
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  description: Vision problems are part of the reported clinical spectrum.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MEF2C-related disorder is characterized by moderate-to-profound developmental delay with
      subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral
      manifestations (autistic features, sleep issues, stereotypic movements particularly of
      the hands), vision issues, and cardiac manifestations.
    explanation: GeneReviews includes visual impairment in the clinical baseline.
- name: Absent speech
  category: Neurological
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  description: >-
    Many individuals do not acquire spoken words; some communicate using a few words or alternative
    methods. The natural-history percentage is age-dependent and is not assumed for regulatory-SV
    cases alone.
  evidence:
  - reference: PMID:35416405
    reference_title: Clinical findings from the landmark MEF2C-related disorders natural history study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: When assessing children over 5 years of age, the majority (82.1%) lacked any spoken words.
    explanation: The parent-reported cohort establishes absent speech in this specified age group.
- name: Inability to walk
  category: Neurological
  phenotype_term:
    preferred_term: Inability to walk
    term:
      id: HP:0002540
      label: Inability to walk
  description: >-
    A substantial subset does not acquire walking. This is distinguished from individuals who
    walk with support.
  evidence:
  - reference: PMID:35416405
    reference_title: Clinical findings from the landmark MEF2C-related disorders natural history study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 17.4% were able to walk with support, and the remaining 42.0% were unable to walk
    explanation: The parent survey distinguishes supported ambulation from inability to walk.
- name: Cardiovascular manifestations
  category: Cardiovascular
  phenotype_term:
    preferred_term: Abnormality of the cardiovascular system
    term:
      id: HP:0001626
      label: Abnormality of the cardiovascular system
    coarse_binding_basis: SOURCE_UNSPECIFIED
  description: >-
    Cardiac involvement is included in the GeneReviews clinical baseline. This aggregate annotation
    follows the nonspecific wording of the cited summary.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MEF2C-related disorder is characterized by moderate-to-profound developmental delay with
      subsequent intellectual disability, hypotonia, dysmorphic features, seizures, neurobehavioral
      manifestations (autistic features, sleep issues, stereotypic movements particularly of
      the hands), vision issues, and cardiac manifestations.
    explanation: The cited GeneReviews summary reports cardiac manifestations without specifying a lesion.
- name: Bruxism
  category: Dental
  phenotype_term:
    preferred_term: Bruxism
    term:
      id: HP:0003763
      label: Bruxism
  description: Bruxism was prominent in the parent-reported natural-history cohort.
  evidence:
  - reference: PMID:35416405
    reference_title: Clinical findings from the landmark MEF2C-related disorders natural history study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Limited speech (82.1%), seizures (86.3%), bruxism (87.7%), repetitive movements (94.5%),
      and high pain tolerance (79.5%) were some of the prominent features.
    explanation: Supports bruxism as a frequent cohort finding.
- name: Reduced pain sensitivity
  category: Neurological
  phenotype_term:
    preferred_term: Impaired pain sensation
    term:
      id: HP:0007328
      label: Impaired pain sensation
  description: High pain tolerance is reported; complete pain insensitivity is not asserted.
  evidence:
  - reference: PMID:35416405
    reference_title: Clinical findings from the landmark MEF2C-related disorders natural history study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Limited speech (82.1%), seizures (86.3%), bruxism (87.7%), repetitive movements (94.5%),
      and high pain tolerance (79.5%) were some of the prominent features.
    explanation: Supports reduced pain sensitivity without requiring complete analgesia.
- name: Feeding difficulties
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  description: Oral feeding can be limited by chewing and swallowing difficulties.
  evidence:
  - reference: PMID:35416405
    reference_title: Clinical findings from the landmark MEF2C-related disorders natural history study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The parents also noted their child had issues with chewing and swallowing, and therefore
      preferred soft or pureed foods.
    explanation: Documents oral feeding difficulties in the parent survey.
- name: Strabismus
  category: Ophthalmological
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  description: Strabismus is among the reported visual abnormalities.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: treatment of refractive errors and strabismus per ophthalmologist
    explanation: >-
      The GeneReviews management summary identifies strabismus as a manifestation requiring
      care.
genetic:
- name: MEF2C
  gene_term:
    preferred_term: MEF2C
    term:
      id: hgnc:6996
      label: MEF2C
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    The MEF2C association includes coding loss of function and proposed expression-mediated
    loss of function from distal rearrangements. Neither rearrangement directly disrupts MEF2C
    coding sequence at a breakpoint. The DGAP218 inversion encompasses MEF2C, so retained coding
    sequence does not mean absence of physical overlap. GeneReviews clinical observations are
    disease-level baseline findings and are not assigned wholesale to either regulatory case.
    Larger upstream deletions can remove additional genes, and require allele-specific assessment
    before attribution of the entire phenotype to MEF2C.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of MEF2C-related disorder is established in a proband by identification
      of a heterozygous pathogenic variant in MEF2C by molecular genetic testing.
    explanation: Establishes the gene-disease association.
  - reference: PMID:30445463
    reference_title: A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett-like characteristics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although, for these very large deletions, deletion of other genes probably contributes
      to the aberrant phenotype
    explanation: Preserves potential contributions from other deleted genes.
  variants:
  - name: DGAP191 translocation affecting MEF2C-AS1 and the MEF2C regulatory domain
    variant_type: translocation
    gene:
      preferred_term: MEF2C-AS1
      term:
        id: hgnc:48908
        label: MEF2C-AS1
    regulatory_target_gene:
      preferred_term: MEF2C
      term:
        id: hgnc:6996
        label: MEF2C
    affected_regions:
    - name: MEF2C-AS1 breakpoint region at 5q14.3
      chromosomal_region: 5q14.3
      within_gene:
        preferred_term: MEF2C-AS1
        term:
          id: hgnc:48908
          label: MEF2C-AS1
      description: >-
        The named region is the 5q14.3 breakpoint interval within the genomic span of MEF2C-AS1.
        It lies in the distal regulatory landscape of MEF2C. It does not denote the entire rearrangement,
        a deleted enhancer, or a precisely localized TAD boundary.
    - name: Upstream MEF2C neuronal regulatory domain
      chromosomal_region: 5q14.3
      description: >-
        The upstream regulatory landscape contains multiple experimentally tested neuronal enhancers
        contacted by the MEF2C promoter. Rearrangements can alter its continuity while leaving
        MEF2C coding sequence intact; different alleles affect different parts of the domain.
    description: >-
      De novo t(5;7)(q14.3;q21.3). Andersen et al. Table 1 reports GRCh38/hg38 breakpoint intervals
      chr5:89411065-89411070 and chr7:94378248-94378255. These are the source-reported breakpoint
      intervals, not a single invented junction. The chr5 break lies within MEF2C-AS1; the chr7
      break overlaps ENSG00000285090. MEF2C coding sequence is intact. The 2024 report reanalyzes
      the same individual studied by Redin et al., not a new independent allele.
    functional_effects:
    - function: MEF2C expression regulation
      description: >-
        MEF2C RNA is reduced in patient LCLs. Enhancer disconnection and interruption of MEF2C-AS1
        are both plausible contributors. MEF2C-AS1 knockdown lowers MEF2C in 293T cells, but
        does not recreate this patient rearrangement or demonstrate its effect in developing
        brain.
      regulatory_mechanism: Distal regulatory-domain rearrangement with lncRNA interruption
    evidence:
    - reference: PMID:39060644
      reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In both cases, the 5q14.3 breakpoints directly disrupt the lncRNA MEF2C-AS1.
      explanation: The primary reanalysis links both named subjects to physical MEF2C-AS1 disruption.
    - reference: PMID:39060644
      reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We additionally identified two cases, DGAP191 and DGAP218, with chromosomal
        rearrangements that disrupt the lncRNA MEF2C-AS1. ...
        t(5;7)(5pter→5q14.3(+)(89,411,06{3–5})::7q21.3(+)(94,378,2{48–50})→7qter;7pter→7q21.3(+)(94,378,25{3–5})::5q14.3(+)(89,411,07{0–2})→5qter)dn
      explanation: >-
        The authors identify the two MEF2C-AS1-disrupting rearrangements in prose; the
        explicit ellipsis separates that statement from this case's derivative-sequence
        notation. The notation preserves the published junction detail, while Table 1
        gives the summarized GRCh38 breakpoint intervals retained in the description.
    - reference: PMID:27841880
      reference_title: The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Correspondingly, in four subjects that harbored BCA breakpoints up to 860 kb distal
        to MEF2C, and for which RNA from lymphoblastoid cell lines (LCLs) was available, MEF2C
        expression was significantly reduced compared to controls
      explanation: Patient-derived LCLs establish an RNA abundance effect.
    - reference: PMID:39060644
      reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Furthermore, we experimentally tested the lncRNAs TBX2-AS1 and MEF2C-AS1 and found that
        knockdown of these lncRNAs resulted in decreased expression of the neighboring transcription
        factors TBX2 and MEF2C, respectively.
      explanation: The independent lncRNA knockdown experiment supports an additional regulatory mechanism.
  - name: DGAP218 inversion affecting MEF2C-AS1 and the MEF2C regulatory domain
    variant_type: inversion
    gene:
      preferred_term: MEF2C-AS1
      term:
        id: hgnc:48908
        label: MEF2C-AS1
    regulatory_target_gene:
      preferred_term: MEF2C
      term:
        id: hgnc:6996
        label: MEF2C
    affected_regions:
    - name: MEF2C-AS1 breakpoint region at 5q14.3
      chromosomal_region: 5q14.3
      within_gene:
        preferred_term: MEF2C-AS1
        term:
          id: hgnc:48908
          label: MEF2C-AS1
      description: >-
        The named region is the 5q14.3 breakpoint interval within the genomic span of MEF2C-AS1.
        It lies in the distal regulatory landscape of MEF2C. It does not denote the entire rearrangement,
        a deleted enhancer, or a precisely localized TAD boundary.
    - name: Upstream MEF2C neuronal regulatory domain
      chromosomal_region: 5q14.3
      description: >-
        The upstream regulatory landscape contains multiple experimentally tested neuronal enhancers
        contacted by the MEF2C promoter. Rearrangements can alter its continuity while leaving
        MEF2C coding sequence intact; different alleles affect different parts of the domain.
    description: >-
      De novo chromosome 5 inversion. Andersen et al. Table 1 reports GRCh38/hg38 breakpoint
      intervals chr5:24272189-24272193 and chr5:89105026-89105031. Its sequence-based interpretation
      places the breakpoints at 5p14.2 and 5q14.3, although the historical karyotype was inv(5)(p12q13.1).
      The published derivative description includes a 15-bp junction insertion, TATTTATATGACAAG.
      MEF2C-AS1 is interrupted while MEF2C coding sequence remains intact. This is the same
      DGAP218 previously studied by Redin et al.
    functional_effects:
    - function: MEF2C expression regulation
      description: >-
        MEF2C RNA is reduced in patient LCLs. Enhancer disconnection and interruption of MEF2C-AS1
        are both plausible contributors. MEF2C-AS1 knockdown lowers MEF2C in 293T cells, but
        does not recreate this patient rearrangement or demonstrate its effect in developing
        brain.
      regulatory_mechanism: Distal regulatory-domain rearrangement with lncRNA interruption
    evidence:
    - reference: PMID:39060644
      reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In both cases, the 5q14.3 breakpoints directly disrupt the lncRNA MEF2C-AS1.
      explanation: The primary reanalysis links both named subjects to physical MEF2C-AS1 disruption.
    - reference: PMID:39060644
      reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We additionally identified two cases, DGAP191 and DGAP218, with chromosomal
        rearrangements that disrupt the lncRNA MEF2C-AS1. ...
        inv(5)(pter→p14.2(+)(24,272,19{3})::q14.3(-)(89,105,02{6})→p14.2(-)(24,272,189)::TATTTATATGACAAG::q14.3(+)(89,105,031)→qter)dn
      explanation: >-
        The authors identify the two MEF2C-AS1-disrupting rearrangements in prose; the
        explicit ellipsis separates that statement from this case's derivative-sequence
        notation. The notation preserves the published junction detail, while Table 1
        gives the summarized GRCh38 breakpoint intervals retained in the description.
    - reference: PMID:27841880
      reference_title: The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Correspondingly, in four subjects that harbored BCA breakpoints up to 860 kb distal
        to MEF2C, and for which RNA from lymphoblastoid cell lines (LCLs) was available, MEF2C
        expression was significantly reduced compared to controls
      explanation: Patient-derived LCLs establish an RNA abundance effect.
    - reference: PMID:39060644
      reference_title: Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Furthermore, we experimentally tested the lncRNAs TBX2-AS1 and MEF2C-AS1 and found that
        knockdown of these lncRNAs resulted in decreased expression of the neighboring transcription
        factors TBX2 and MEF2C, respectively.
      explanation: The independent lncRNA knockdown experiment supports an additional regulatory mechanism.
diagnosis:
- name: Molecular genetic diagnosis
  description: >-
    Molecular testing identifies a heterozygous pathogenic MEF2C variant in the established
    coding/deletion disorder. Variant interpretation must fit the clinical findings.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of MEF2C-related disorder is established in a proband by identification
      of a heterozygous pathogenic variant in MEF2C by molecular genetic testing.
    explanation: Provides the baseline diagnostic criterion.
- name: Structural variant and breakpoint assessment
  description: >-
    In a compatible phenotype with intact MEF2C coding sequence, assessment of balanced rearrangements
    and distal copy-number changes can identify a regulatory hypothesis. Breakpoint mapping,
    the other affected loci, and functional evidence matter; overlap with the domain alone does
    not establish a diagnosis.
  evidence:
  - reference: PMID:27841880
    reference_title: The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data strongly argue for the implementation of technologies capable of detecting
      both balanced and unbalanced genomic rearrangements.
    explanation: Supports structural-variant detection beyond sequence variants.
  - reference: PMID:30445463
    reference_title: A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett-like characteristics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Structural variants (SVs) upstream of MEF2C, which do not disrupt the gene itself, have
      also been found in patients with a similar phenotype, suggesting that disruption of MEF2C
      regulatory elements can also cause a Rett-like phenotype.
    explanation: Supports considering distal structural variants in the relevant phenotype.
treatments:
- name: Developmental and rehabilitation support
  description: >-
    Developmental and educational services, physical and occupational therapy, and individualized
    communication support address functional needs.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Developmental and educational services; treatment of gait abnormalities per orthopedist,
      physical medicine and rehabilitation specialist, and/or physical or occupational therapist
    explanation: Supports multidisciplinary developmental and motor care.
- name: Individualized seizure management
  description: >-
    Seizures receive standard treatment tailored to seizure type and response; this entry does
    not assert a specific preferred drug for regulatory-SV disease.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: standard treatment for gastroesophageal reflux disease, constipation, and seizures
    explanation: GeneReviews recommends standard symptomatic seizure management.
- name: Feeding and gastrointestinal support
  description: >-
    Assess oral feeding safety and nutritional needs, provide feeding support, and treat reflux
    or constipation when present.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      feeding support as needed; standard treatment for gastroesophageal reflux disease, constipation,
      and seizures
    explanation: Supports feeding and gastrointestinal care.
- name: Cardiac, visual, and infection-directed care
  description: >-
    Cardiology and ophthalmology care are guided by individual findings. Recurrent respiratory
    or ear infections warrant standard treatment and hearing assessment when indicated.
  evidence:
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      treatment of cardiac manifestations per cardiologist; treatment of refractive errors and
      strabismus per ophthalmologist
    explanation: Supports specialist care for documented cardiac and visual manifestations.
  - reference: PMID:39666846
    reference_title: MEF2C-Related Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: antibiotics as needed for recurrent respiratory infections and recurrent otitis media
    explanation: Supports treatment of recurrent infections as required.
references:
- reference: PMID:39666846
  title: MEF2C-Related Disorder.
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:39666846
MEF2C-Related Disorder.
No top-level findings curated for this source.