Intellectual developmental disorder 60 with seizures

Summary

Intellectual developmental disorder 60 with seizures (MONDO:0032823) is a disease caused by AP2M1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: AP2M1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual developmental disorder 60 with seizures
Mondo ID	MONDO:0032823
OMIM	618587
DOID	DOID:0061050
UMLS	C5231497
MedGen	1684702
GARD	0016367
Is cancer (heuristic)	no

Also known as: MRD60

Data availability: 20 ClinVar variants · 5 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 60 with seizures

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 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

20 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 7 benign, 1 benign/likely benign, 1 likely benign, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
689722	NM_004068.4(AP2M1):c.508C>T (p.Arg170Trp)	AP2M1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3064175	NM_001135638.2(PIP5K1A):c.1114C>T (p.Arg372Ter)	PIP5K1A	Likely pathogenic	criteria provided, single submitter
1285449	NM_004068.4(AP2M1):c.73G>A (p.Gly25Arg)	AP2M1	Uncertain significance	criteria provided, single submitter
1299229	NM_004068.4(AP2M1):c.911A>C (p.Lys304Thr)	AP2M1	Uncertain significance	criteria provided, single submitter
1708107	NM_004068.4(AP2M1):c.538A>T (p.Ser180Cys)	AP2M1	Uncertain significance	criteria provided, single submitter
2439134	NM_004068.4(AP2M1):c.916G>A (p.Val306Ile)	AP2M1	Uncertain significance	criteria provided, single submitter
3024240	NM_004068.4(AP2M1):c.1087G>C (p.Glu363Gln)	AP2M1	Uncertain significance	criteria provided, single submitter
3254703	NM_004068.4(AP2M1):c.97C>T (p.Arg33Trp)	AP2M1	Uncertain significance	criteria provided, single submitter
3362496	NM_004068.4(AP2M1):c.178C>T (p.Arg60Trp)	AP2M1	Uncertain significance	criteria provided, single submitter
3901053	NM_004068.4(AP2M1):c.596G>A (p.Arg199Gln)	AP2M1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4082058	NM_004068.4(AP2M1):c.61C>T (p.Arg21Ter)	AP2M1	Uncertain significance	no assertion criteria provided
1170246	NM_004068.4(AP2M1):c.1293T>C (p.Tyr431=)	AP2M1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1192404	NM_004068.4(AP2M1):c.960C>T (p.Ile320=)	AP2M1	Benign	criteria provided, multiple submitters, no conflicts
1192405	NM_004068.4(AP2M1):c.1173+73T>C	AP2M1	Benign	criteria provided, multiple submitters, no conflicts
1192406	NM_004068.4(AP2M1):c.1185G>A (p.Ala395=)	AP2M1	Benign	criteria provided, multiple submitters, no conflicts
1283914	NM_004068.4(AP2M1):c.529G>T (p.Val177Leu)	AP2M1	Likely benign	no assertion criteria provided
1598839	NM_004068.4(AP2M1):c.565+17G>A	AP2M1	Benign	criteria provided, multiple submitters, no conflicts
1610043	NM_004068.4(AP2M1):c.75-4T>C	AP2M1	Benign	criteria provided, multiple submitters, no conflicts
1693169	NM_004068.4(AP2M1):c.340+56G>A	AP2M1	Benign	criteria provided, single submitter
1693170	NM_004068.4(AP2M1):c.707+56G>T	AP2M1	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
AP2M1	Strong	Autosomal dominant	intellectual developmental disorder 60 with seizures	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AP2M1	Orphanet:1942	Epilepsy with myoclonic-atonic seizures

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
AP2M1	HGNC:564	ENSG00000161203	Q96CW1	AP-2 complex subunit mu	gencc,clinvar
PIP5K1A	HGNC:8994	ENSG00000143398	Q99755	Phosphatidylinositol 4-phosphate 5-kinase type-1 alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AP2M1	AP-2 complex subunit mu	Component of the adaptor protein complex 2 (AP-2).
PIP5K1A	Phosphatidylinositol 4-phosphate 5-kinase type-1 alpha	Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2/PIP2), a lipid second messenger that regulates several cellular processes such as signal trans…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AP2M1	Other/Unknown	no		Clathrin_mu, Longin-like_dom_sf, Clathrin_mu_CS
PIP5K1A	Kinase	yes	2.7.1.68	PInositol-4-P-4/5-kinase_core, PInositol-4/5-P-5/4-kinase, PInositol-4-P-4/5-kinase_C_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
prefrontal cortex	1
right frontal lobe	1
right hemisphere of cerebellum	1
adrenal tissue	1
colonic epithelium	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AP2M1	300	ubiquitous	marker	right frontal lobe, prefrontal cortex, right hemisphere of cerebellum
PIP5K1A	274	ubiquitous	marker	right testis, colonic epithelium, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIP5K1A	1,811
AP2M1	1,158

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AP2M1	Q96CW1	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PIP5K1A	Q99755	70.92

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. 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
Nef mediated downregulation of CD28 cell surface expression	1	2855.0×	0.013	AP2M1
Nef Mediated CD8 Down-regulation	1	815.7×	0.013	AP2M1
Nef Mediated CD4 Down-regulation	1	634.4×	0.013	AP2M1
Formation of annular gap junctions	1	519.1×	0.013	AP2M1
Gap junction degradation	1	475.8×	0.013	AP2M1
WNT5A-dependent internalization of FZD2, FZD5 and ROR2	1	439.2×	0.013	AP2M1
Retrograde neurotrophin signalling	1	407.9×	0.013	AP2M1
WNT5A-dependent internalization of FZD4	1	380.7×	0.013	AP2M1
VLDLR internalisation and degradation	1	356.9×	0.013	AP2M1
Trafficking of GluR2-containing AMPA receptors	1	335.9×	0.013	AP2M1
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1	317.2×	0.013	AP2M1
The role of Nef in HIV-1 replication and disease pathogenesis	1	317.2×	0.013	AP2M1
LDL clearance	1	271.9×	0.013	AP2M1
Gap junction trafficking and regulation	1	237.9×	0.013	AP2M1
Gap junction trafficking	1	237.9×	0.013	AP2M1
Plasma lipoprotein clearance	1	237.9×	0.013	AP2M1
Host Interactions of HIV factors	1	167.9×	0.017	AP2M1
PCP/CE pathway	1	150.3×	0.018	AP2M1
Beta-catenin independent WNT signaling	1	146.4×	0.018	AP2M1
Dengue Virus Attachment and Entry	1	129.8×	0.019	AP2M1
Plasma lipoprotein assembly, remodeling, and clearance	1	114.2×	0.019	AP2M1
Recycling pathway of L1	1	112.0×	0.019	AP2M1
EPH-ephrin mediated repulsion of cells	1	109.8×	0.019	AP2M1
Synthesis of PIPs at the plasma membrane	1	105.7×	0.019	PIP5K1A
Signaling by NTRK1 (TRKA)	1	98.5×	0.020	AP2M1
Signaling by NTRKs	1	90.6×	0.021	AP2M1
EPH-Ephrin signaling	1	82.8×	0.022	AP2M1
L1CAM interactions	1	60.1×	0.028	AP2M1
HIV Infection	1	59.5×	0.028	AP2M1
Potential therapeutics for SARS	1	57.1×	0.028	AP2M1

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
glycerophospholipid metabolic process	1	1404.3×	0.007	PIP5K1A
positive regulation of synaptic vesicle endocytosis	1	1404.3×	0.007	AP2M1
regulation of vesicle size	1	1203.7×	0.007	AP2M1
postsynaptic neurotransmitter receptor internalization	1	1053.2×	0.007	AP2M1
ruffle assembly	1	648.1×	0.007	PIP5K1A
vesicle budding from membrane	1	561.7×	0.007	AP2M1
fibroblast migration	1	421.3×	0.007	PIP5K1A
activation of GTPase activity	1	366.4×	0.007	PIP5K1A
positive regulation of receptor internalization	1	351.1×	0.007	AP2M1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	351.1×	0.007	PIP5K1A
phospholipid biosynthetic process	1	337.0×	0.007	PIP5K1A
negative regulation of protein localization to plasma membrane	1	312.1×	0.007	AP2M1
clathrin-dependent endocytosis	1	290.6×	0.007	AP2M1
focal adhesion assembly	1	263.3×	0.008	PIP5K1A
phosphatidylinositol phosphate biosynthetic process	1	240.7×	0.008	PIP5K1A
synaptic vesicle endocytosis	1	216.1×	0.008	AP2M1
phosphatidylinositol biosynthetic process	1	183.2×	0.009	PIP5K1A
receptor internalization	1	162.0×	0.010	AP2M1
keratinocyte differentiation	1	123.9×	0.012	PIP5K1A
phagocytosis	1	120.4×	0.012	PIP5K1A
cell chemotaxis	1	92.6×	0.014	PIP5K1A
protein-containing complex assembly	1	56.9×	0.022	AP2M1
protein localization to plasma membrane	1	54.4×	0.022	PIP5K1A
vesicle-mediated transport	1	48.1×	0.024	AP2M1
actin cytoskeleton organization	1	39.6×	0.028	PIP5K1A
intracellular protein transport	1	32.4×	0.033	AP2M1
cell migration	1	30.8×	0.033	PIP5K1A
signal transduction	1	8.0×	0.121	PIP5K1A

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PIP5K1A	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIP5K1A	15	4
AP2M1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	PIP5K1A
BOSUTINIB	4	PIP5K1A
NINTEDANIB	4	PIP5K1A
SUNITINIB	4	PIP5K1A
CRIZOTINIB	4	PIP5K1A
MIDOSTAURIN	4	PIP5K1A
DOVITINIB	3	PIP5K1A
LESTAURTINIB	3	PIP5K1A
RUBOXISTAURIN	3	PIP5K1A
SU-014813	2	PIP5K1A
TG100-115	2	PIP5K1A
R-406	2	PIP5K1A
TOZASERTIB	2	PIP5K1A
GSK-461364	1	PIP5K1A
KW-2449	1	PIP5K1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PIP5K1A	119	Binding:119
AP2M1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PIP5K1A	2.7.1.68	1-phosphatidylinositol-4-phosphate 5-kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PIP5K1A	119

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

15 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)
FEDRATINIB	4	PIP5K1A
BOSUTINIB	4	PIP5K1A
NINTEDANIB	4	PIP5K1A
SUNITINIB	4	PIP5K1A
CRIZOTINIB	4	PIP5K1A
MIDOSTAURIN	4	PIP5K1A
DOVITINIB	3	PIP5K1A
LESTAURTINIB	3	PIP5K1A
RUBOXISTAURIN	3	PIP5K1A
SU-014813	2	PIP5K1A
TG100-115	2	PIP5K1A
R-406	2	PIP5K1A
TOZASERTIB	2	PIP5K1A
GSK-461364	1	PIP5K1A
KW-2449	1	PIP5K1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PIP5K1A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	AP2M1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AP2M1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.