Intellectual developmental disorder 62

Summary

Intellectual developmental disorder 62 (MONDO:0032919) is a disease caused by DLG4 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: DLG4 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 120

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual developmental disorder 62
Mondo ID	MONDO:0032919
OMIM	618793
DOID	DOID:0061035
ICD-10-CM	QA0.0142
UMLS	C5394083
MedGen	1712636
GARD	0025775
Is cancer (heuristic)	no

Also known as: autosomal dominant intellectual developmental disorder-62 · DLG4 synaptopathy · DLG4-related synaptopathy · intellectual developmental disorder, autosomal dominant 62 · Mental Retardation, Autosomal Dominant 62 · MRD62 · SHINE syndrome · sleep disturbances, hypotonia, intellectual disability, neurologic disorder, and epilepsy syndrome

Data availability: 120 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 › intellectual developmental disorder 62

Related subtypes (25): intellectual disability, autosomal dominant 22, neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language, 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, 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

120 retrieved; paginated sample, class counts are floors:

43 pathogenic, 30 uncertain significance, 20 pathogenic/likely pathogenic, 20 likely pathogenic, 3 conflicting classifications of pathogenicity, 2 benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1164039	NM_001321075.3(DLG4):c.1083G>A (p.Ser361=)	DLG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1285581	NM_001321075.3(DLG4):c.1866+2T>C	DLG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1300623	NM_001321075.3(DLG4):c.1072C>T (p.Gln358Ter)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1305865	NM_001321075.3(DLG4):c.642G>A (p.Ala214=)	DLG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1308653	NM_001321075.3(DLG4):c.530G>T (p.Gly177Val)	DLG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324230	NM_001321075.3(DLG4):c.1486C>T (p.Arg496Ter)	DLG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325828	NM_001321075.3(DLG4):c.1849C>T (p.Arg617Ter)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329878	NM_001321075.3(DLG4):c.193G>T (p.Glu65Ter)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329879	NM_001321075.3(DLG4):c.211-2A>G	DLG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329880	NM_001321075.3(DLG4):c.218C>G (p.Ser73Ter)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329881	NM_001321075.3(DLG4):c.243dup (p.Gly82fs)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329882	NM_001321075.3(DLG4):c.319C>T (p.Gln107Ter)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329883	NM_001321075.3(DLG4):c.339del (p.Asn114fs)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329884	NM_001321075.3(DLG4):c.478G>T (p.Glu160Ter)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329886	NM_001321075.3(DLG4):c.557A>T (p.Asp186Val)	DLG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329888	NM_001321075.3(DLG4):c.787+2T>C	DLG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329889	NM_001321075.3(DLG4):c.792T>A (p.Tyr264Ter)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329891	NM_001321075.3(DLG4):c.1084-1G>T	DLG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329892	NM_001321075.3(DLG4):c.1195C>T (p.Arg399Ter)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329893	NM_001321075.3(DLG4):c.1458del (p.Phe487fs)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329894	NM_001321075.3(DLG4):c.1478+2T>C	DLG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329897	NM_001321075.3(DLG4):c.1497G>A (p.Trp499Ter)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329898	NM_001321075.3(DLG4):c.1496G>A (p.Trp499Ter)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329899	NM_001321075.3(DLG4):c.1592-1G>A	DLG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329900	NM_001321075.3(DLG4):c.1672A>T (p.Lys558Ter)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329901	NM_001321075.3(DLG4):c.1693+1G>A	DLG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329902	NM_001321075.3(DLG4):c.1757G>A (p.Arg586Gln)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329903	NM_001321075.3(DLG4):c.1832C>T (p.Thr611Ile)	DLG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329905	NM_001321075.3(DLG4):c.1855del (p.Val619fs)	DLG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1329906	NM_001321075.3(DLG4):c.1878C>A (p.Cys626Ter)	DLG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
DLG4	Strong	Autosomal dominant	intellectual developmental disorder 62	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DLG4	Orphanet:528084	Non-specific syndromic intellectual disability
ACADVL	Orphanet:26793	Very long chain acyl-CoA dehydrogenase deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DLG4	HGNC:2903	ENSG00000132535	P78352	Disks large homolog 4	gencc,clinvar
ACADVL	HGNC:92	ENSG00000072778	P49748	Very long-chain acyl-CoA dehydrogenase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DLG4	Disks large homolog 4	Postsynaptic scaffolding protein that plays a critical role in synaptogenesis and synaptic plasticity by providing a platform for the postsynaptic clustering of crucial synaptic proteins.
ACADVL	Very long-chain acyl-CoA dehydrogenase, mitochondrial	Very long-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation (FAO), breaking down fatty acids into acetyl-CoA and allowing the production of e…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	13.9×	0.142
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DLG4	Kinase	yes		SH3_domain, PDZ, Guanylate_kin-like_dom
ACADVL	Enzyme (other)	yes	1.3.8.8	Acyl-CoA_DH_CS, AcylCoA_DH/ox_M, AcylCo_DH/oxidase_C

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
apex of heart	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DLG4	190	tissue_specific	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ACADVL	295	ubiquitous	marker	right adrenal gland cortex, apex of heart, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DLG4	6,905
ACADVL	2,988

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DLG4	P78352	24
ACADVL	P49748	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Beta oxidation of palmitoyl-CoA to myristoyl-CoA	1	1903.3×	0.008	ACADVL
NrCAM interactions	1	815.7×	0.008	DLG4
mitochondrial fatty acid beta-oxidation of saturated fatty acids	1	815.7×	0.008	ACADVL
Activation of Ca-permeable Kainate Receptor	1	571.0×	0.008	DLG4
LGI-ADAM interactions	1	407.9×	0.008	DLG4
RHO GTPases activate CIT	1	300.5×	0.008	DLG4
Ras activation upon Ca2+ influx through NMDA receptor	1	285.5×	0.008	DLG4
Trafficking of AMPA receptors	1	271.9×	0.008	DLG4
Unblocking of NMDA receptors, glutamate binding and activation	1	271.9×	0.008	DLG4
Synaptic adhesion-like molecules	1	271.9×	0.008	DLG4
Negative regulation of NMDA receptor-mediated neuronal transmission	1	271.9×	0.008	DLG4
IRE1alpha activates chaperones	1	259.6×	0.008	ACADVL
Long-term potentiation	1	237.9×	0.008	DLG4
Mitochondrial Fatty Acid Beta-Oxidation	1	190.3×	0.009	ACADVL
Unfolded Protein Response (UPR)	1	178.4×	0.009	ACADVL
Signaling by ERBB4	1	135.9×	0.011	DLG4
Assembly and cell surface presentation of NMDA receptors	1	126.9×	0.012	DLG4
XBP1(S) activates chaperone genes	1	107.7×	0.013	ACADVL
Neurexins and neuroligins	1	98.5×	0.013	DLG4
Fatty acid metabolism	1	65.6×	0.019	ACADVL
RAF/MAP kinase cascade	1	30.5×	0.039	DLG4
Cellular responses to stress	1	18.4×	0.061	ACADVL
Metabolism of lipids	1	15.8×	0.065	ACADVL
Cellular responses to stimuli	1	15.7×	0.065	ACADVL
Metabolism	1	5.8×	0.165	ACADVL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
energy derivation by oxidation of organic compounds	1	4213.0×	0.005	ACADVL
regulation of grooming behavior	1	2808.7×	0.005	DLG4
AMPA glutamate receptor clustering	1	1685.2×	0.005	DLG4
NMDA selective glutamate receptor signaling pathway	1	1203.7×	0.005	DLG4
receptor localization to synapse	1	1053.2×	0.005	DLG4
positive regulation of neuron projection arborization	1	1053.2×	0.005	DLG4
synaptic vesicle maturation	1	936.2×	0.005	DLG4
negative regulation of fatty acid oxidation	1	842.6×	0.005	ACADVL
fatty acid beta-oxidation using acyl-CoA dehydrogenase	1	702.2×	0.005	ACADVL
negative regulation of receptor internalization	1	601.9×	0.005	DLG4
positive regulation of synaptic transmission	1	561.7×	0.005	DLG4
regulation of cholesterol metabolic process	1	561.7×	0.005	ACADVL
cellular response to potassium ion	1	526.6×	0.005	DLG4
locomotory exploration behavior	1	495.6×	0.005	DLG4
regulation of long-term neuronal synaptic plasticity	1	495.6×	0.005	DLG4
negative regulation of fatty acid biosynthetic process	1	443.5×	0.005	ACADVL
dendritic spine morphogenesis	1	443.5×	0.005	DLG4
vocalization behavior	1	443.5×	0.005	DLG4
neurotransmitter receptor localization to postsynaptic specialization membrane	1	401.2×	0.005	DLG4
protein localization to synapse	1	383.0×	0.005	DLG4
temperature homeostasis	1	324.1×	0.005	ACADVL
establishment or maintenance of epithelial cell apical/basal polarity	1	290.6×	0.006	DLG4
response to cold	1	280.9×	0.006	ACADVL
positive regulation of excitatory postsynaptic potential	1	263.3×	0.006	DLG4
regulation of postsynaptic membrane neurotransmitter receptor levels	1	247.8×	0.006	DLG4
establishment of protein localization	1	216.1×	0.006	DLG4
neuromuscular process controlling balance	1	165.2×	0.008	DLG4
learning	1	140.4×	0.009	DLG4
social behavior	1	135.9×	0.009	DLG4
epithelial cell differentiation	1	87.8×	0.014	ACADVL

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DLG4	1	3
ACADVL	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NERINETIDE	3	DLG4
TG100-115	2	ACADVL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DLG4	20	Binding:20
ACADVL	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACADVL	1.3.8.8, 1.3.8.9	long-chain acyl-CoA dehydrogenase, very-long-chain acyl-CoA dehydrogenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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.

Compound	Max phase	Cohort target (bioactivity)
NERINETIDE	3	DLG4
TG100-115	2	ACADVL

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	2	DLG4, ACADVL
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.