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

Summary

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (MONDO:0013266) is a disease caused by MEF2C (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: MEF2C (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 454

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language
Mondo ID	MONDO:0013266
OMIM	613443
Orphanet	664410
DOID	DOID:0070050
UMLS	C3150700
MedGen	462050
GARD	0024910
NORD	2013
Is cancer (heuristic)	no

Also known as: autosomal dominant non-syndromic intellectual disability caused by mutation in MEF2C · intellectual disability, autosomal dominant 20 · intellectual disability, autosomal dominant type 20 · MEF2C autosomal dominant non-syndromic intellectual disability · MEF2C Deficiency · MEF2C haploinsufficiency syndrome (MCHS) · MEF2C-related neurodevelopmental disorder · MEF2C-related syndrome · mental retardation, autosomal dominant 20 · mental retardation, autosomal dominant type 20 · mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations · MRD20 · neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language

Data availability: 454 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › autosomal dominant non-syndromic intellectual disability › neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language

Related subtypes (25): intellectual disability, autosomal dominant 22, intellectual disability, autosomal dominant 33, intellectual disability, autosomal dominant 34, intellectual disability, autosomal dominant 41, intellectual disability, autosomal dominant 43, intellectual disability, autosomal dominant 58, intellectual disability, autosomal dominant 45, intellectual disability, autosomal dominant 46, intellectual disability, autosomal dominant 47, Clark-Baraitser syndrome, intellectual disability, autosomal dominant 50, intellectual disability, autosomal dominant 51, intellectual disability, autosomal dominant 52, intellectual disability, autosomal dominant 53, intellectual disability, autosomal dominant 54, intellectual disability, autosomal dominant 55, with seizures, intellectual disability, autosomal dominant 56, intellectual developmental disorder 61, intellectual developmental disorder 59, intellectual developmental disorder 60 with seizures, intellectual developmental disorder 62, intellectual developmental disorder, autosomal dominant 63, with macrocephaly, Coffin-Siris syndrome 6, intellectual disability, autosomal dominant 57, intellectual developmental disorder, autosomal dominant 73

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

454 retrieved; paginated sample, class counts are floors:

179 likely benign, 121 uncertain significance, 62 pathogenic, 30 likely pathogenic, 25 conflicting classifications of pathogenicity, 19 benign, 8 pathogenic/likely pathogenic, 8 benign/likely benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1707717	NC_000005.9:g.(?88625195)(90796047_?)inv	ADGRV1	Pathogenic	criteria provided, single submitter
2579178	GRCh38/hg38 5q14.3-15(chr5:88189536-93784597)x1	ADGRV1	Pathogenic	criteria provided, single submitter
3256134	Single allele	LOC129994183	Pathogenic	criteria provided, single submitter
598760	NC_000005.10:g.88846693_89051376delinsG	LOC129994186	Pathogenic	criteria provided, single submitter
1066205	NM_002397.5(MEF2C):c.638-1G>A	MEF2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070269	NC_000005.9:g.(?87776690)(88119605_?)del	MEF2C	Pathogenic	criteria provided, single submitter
1070711	NM_002397.5(MEF2C):c.559dup (p.Thr187fs)	MEF2C	Pathogenic	criteria provided, single submitter
1072396	NC_000005.9:g.(?88027526)(88027738_?)del	MEF2C	Pathogenic	criteria provided, single submitter
1202675	NM_002397.5(MEF2C):c.-8C>T	MEF2C	Pathogenic	criteria provided, multiple submitters, no conflicts
1272069	NM_002397.5(MEF2C):c.220G>T (p.Glu74Ter)	MEF2C	Pathogenic	no assertion criteria provided
1272071	NM_002397.5(MEF2C):c.-26C>T	MEF2C	Pathogenic	criteria provided, multiple submitters, no conflicts
1272072	NM_002397.5(MEF2C):c.-66A>T	MEF2C	Pathogenic	no assertion criteria provided
1412055	NC_000005.9:g.(?88047654)(88047880_?)del	MEF2C	Pathogenic	criteria provided, single submitter
158886	NM_002397.5(MEF2C):c.565C>T (p.Arg189Ter)	MEF2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158888	NM_002397.5(MEF2C):c.833del (p.Leu277_Leu278insTer)	MEF2C	Pathogenic	criteria provided, multiple submitters, no conflicts
1685375	NM_002397.5(MEF2C):c.104T>C (p.Leu35Pro)	MEF2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685944	NM_002397.5(MEF2C):c.44G>C (p.Arg15Pro)	MEF2C	Pathogenic	criteria provided, multiple submitters, no conflicts
1703661	GRCh37/hg19 5q14.3(chr5:88065061-88406446)	MEF2C	Pathogenic	no assertion criteria provided
1805133	NM_002397.5(MEF2C):c.908del (p.Leu303fs)	MEF2C	Pathogenic	criteria provided, single submitter
1805734	NM_002397.5(MEF2C):c.939_940del (p.Ala314fs)	MEF2C	Pathogenic	criteria provided, single submitter
1992493	NC_000005.10:g.88731902del	MEF2C	Pathogenic	criteria provided, single submitter
2001170	NM_002397.5(MEF2C):c.468del (p.Tyr157fs)	MEF2C	Pathogenic	criteria provided, single submitter
2007342	NM_002397.5(MEF2C):c.999_1000del (p.Ser334fs)	MEF2C	Pathogenic	criteria provided, single submitter
206129	NM_002397.5(MEF2C):c.43C>T (p.Arg15Cys)	MEF2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206134	NM_002397.5(MEF2C):c.766C>T (p.Arg256Ter)	MEF2C	Pathogenic	criteria provided, multiple submitters, no conflicts
2091785	NM_002397.5(MEF2C):c.881del (p.Pro294fs)	MEF2C	Pathogenic	criteria provided, single submitter
211494	NM_002397.5(MEF2C):c.2T>C (p.Met1Thr)	MEF2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2169514	NM_002397.5(MEF2C):c.79G>A (p.Gly27Arg)	MEF2C	Pathogenic	criteria provided, multiple submitters, no conflicts
218315	NM_002397.5(MEF2C):c.9A>T (p.Arg3Ser)	MEF2C	Pathogenic	no assertion criteria provided
224136	NM_002397.5(MEF2C):c.71G>A (p.Arg24Lys)	MEF2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MEF2C	Definitive	Autosomal dominant	neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MEF2C	Orphanet:228384	5q14.3 microdeletion syndrome
MEF2C	Orphanet:576227	Complete atrioventricular septal defect without ventricular hypoplasia
MEF2C	Orphanet:664416	Brain abnormalities-severe developmental delay-facial dysmorphism-intellectual disability syndrome due to MEF2C mutation
ADGRV1	Orphanet:231178	Usher syndrome type 2
ADGRV1	Orphanet:36387	Genetic epilepsy with febrile seizure plus
FAM13A	Orphanet:2032	Idiopathic pulmonary fibrosis

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MEF2C	HGNC:6996	ENSG00000081189	Q06413	Myocyte-specific enhancer factor 2C	gencc,clinvar
ADGRV1	HGNC:17416	ENSG00000164199	Q8WXG9	Adhesion G-protein coupled receptor V1	clinvar
FAM13A	HGNC:19367	ENSG00000138640	O94988	Protein FAM13A	clinvar
MEF2C-AS2	HGNC:53115	ENSG00000245864		MEF2C antisense RNA 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MEF2C	Myocyte-specific enhancer factor 2C	Transcription activator which binds specifically to the MEF2 element present in the regulatory regions of many muscle-specific genes.
ADGRV1	Adhesion G-protein coupled receptor V1	G-protein coupled receptor which has an essential role in the development of hearing and vision.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
GPCR	1	6.0×	0.471
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MEF2C	Transcription factor	no		TF_MADSbox, HJURP_C, MEF2-like_N
ADGRV1	GPCR	yes		GPCR_2_secretin-like, Calx_beta, EPTP
FAM13A	Other/Unknown	no		RhoGAP_dom, Rho_GTPase_activation_prot, FAM13
MEF2C-AS2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
gluteal muscle	1
middle temporal gyrus	1
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
jejunal mucosa	1
oocyte	1
secondary oocyte	1
ganglionic eminence	1
male germ line stem cell (sensu Vertebrata) in testis	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MEF2C	283	ubiquitous	marker	middle temporal gyrus, gluteal muscle, biceps brachii
ADGRV1	196	broad	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
FAM13A	293	ubiquitous	marker	secondary oocyte, oocyte, jejunal mucosa
MEF2C-AS2	126	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, ventricular zone, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MEF2C	4,063
ADGRV1	1,658
FAM13A	830
MEF2C-AS2	0

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FAM13A	O94988	61.00
MEF2C	Q06413	56.80
ADGRV1	Q8WXG9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. Enrichment computed across 4 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MECP2 regulates transcription factors	1	761.3×	0.028	MEF2C
ERK/MAPK targets	1	223.9×	0.028	MEF2C
MAPK targets/ Nuclear events mediated by MAP kinases	1	181.3×	0.028	MEF2C
Cardiogenesis	1	141.0×	0.028	MEF2C
Myogenesis	1	126.9×	0.028	MEF2C
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	122.8×	0.028	ADGRV1
Nuclear Events (kinase and transcription factor activation)	1	115.3×	0.028	MEF2C
R-HSA-400253	1	115.3×	0.028	MEF2C
Transcriptional Regulation by MECP2	1	105.7×	0.028	MEF2C
MAP kinase activation	1	102.9×	0.028	MEF2C
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	97.6×	0.028	MEF2C
Interleukin-17 signaling	1	84.6×	0.028	MEF2C
Toll Like Receptor 10 (TLR10) Cascade	1	71.8×	0.028	MEF2C
Toll Like Receptor 5 (TLR5) Cascade	1	71.8×	0.028	MEF2C
Heme signaling	1	71.8×	0.028	MEF2C
Transcriptional activation of mitochondrial biogenesis	1	68.0×	0.028	MEF2C
MyD88 cascade initiated on plasma membrane	1	68.0×	0.028	MEF2C
Signaling by NTRK1 (TRKA)	1	65.6×	0.028	MEF2C
Toll Like Receptor 3 (TLR3) Cascade	1	64.5×	0.028	MEF2C
TRIF (TICAM1)-mediated TLR4 signaling	1	63.4×	0.028	MEF2C
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1	63.4×	0.028	MEF2C
MyD88 dependent cascade initiated on endosome	1	63.4×	0.028	MEF2C
MyD88-independent TLR4 cascade	1	61.4×	0.028	MEF2C
Toll Like Receptor 7/8 (TLR7/8) Cascade	1	61.4×	0.028	MEF2C
Signaling by NTRKs	1	60.4×	0.028	MEF2C
Toll Like Receptor 9 (TLR9) Cascade	1	58.6×	0.028	MEF2C
Toll Like Receptor TLR6:TLR2 Cascade	1	58.6×	0.028	MEF2C
Toll Like Receptor 2 (TLR2) Cascade	1	57.7×	0.028	MEF2C
Mitochondrial biogenesis	1	56.0×	0.028	MEF2C
Toll Like Receptor TLR1:TLR2 Cascade	1	56.0×	0.028	MEF2C

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of bone mineralization	2	261.3×	0.002	MEF2C, ADGRV1
cellular response to calcium ion	2	133.8×	0.004	MEF2C, ADGRV1
sinoatrial valve morphogenesis	1	5617.3×	0.005	MEF2C
muscle cell fate determination	1	2808.7×	0.005	MEF2C
nephron tubule epithelial cell differentiation	1	2808.7×	0.005	MEF2C
primary heart field specification	1	1872.4×	0.005	MEF2C
cardiac ventricle formation	1	1872.4×	0.005	MEF2C
cellular response to trichostatin A	1	1872.4×	0.005	MEF2C
glomerulus morphogenesis	1	1872.4×	0.005	MEF2C
positive regulation of macrophage apoptotic process	1	1872.4×	0.005	MEF2C
positive regulation of skeletal muscle cell differentiation	1	1872.4×	0.005	MEF2C
regulation of synaptic activity	1	1404.3×	0.005	MEF2C
renal tubule morphogenesis	1	1404.3×	0.005	MEF2C
maintenance of animal organ identity	1	1123.5×	0.005	ADGRV1
inner ear receptor cell differentiation	1	1123.5×	0.005	ADGRV1
AMPA selective glutamate receptor signaling pathway	1	1123.5×	0.005	MEF2C
negative regulation of vascular endothelial cell proliferation	1	1123.5×	0.005	MEF2C
epithelial cell proliferation involved in renal tubule morphogenesis	1	1123.5×	0.005	MEF2C
regulation of germinal center formation	1	936.2×	0.005	MEF2C
positive regulation of skeletal muscle tissue development	1	936.2×	0.005	MEF2C
ventricular cardiac muscle cell differentiation	1	802.5×	0.005	MEF2C
NMDA selective glutamate receptor signaling pathway	1	802.5×	0.005	MEF2C
positive regulation of cardiac muscle cell differentiation	1	802.5×	0.005	MEF2C
positive regulation of behavioral fear response	1	802.5×	0.005	MEF2C
myotube differentiation	1	702.2×	0.006	MEF2C
nervous system development	2	30.6×	0.006	MEF2C, ADGRV1
regulation of megakaryocyte differentiation	1	624.1×	0.006	MEF2C
sensory perception of light stimulus	1	624.1×	0.006	ADGRV1
germinal center formation	1	561.7×	0.006	MEF2C
regulation of dendritic spine development	1	561.7×	0.006	MEF2C

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 0 of 4 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MEF2C	0	0
ADGRV1	0	0
FAM13A	0	0
MEF2C-AS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ADGRV1
E	Difficult family or no structure, no drug	3	MEF2C, FAM13A, MEF2C-AS2

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MEF2C	0	—
ADGRV1	0	—
FAM13A	0	—
MEF2C-AS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.