Intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Summary

Intellectual disability-hypotonia-spasticity-sleep disorder syndrome (MONDO:0014210) is a disease caused by ANK3 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ANK3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 129
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000718	Aggressive behavior	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000752	Hyperactivity	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0003763	Bruxism	Frequent (30-79%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001520	Large for gestational age	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability-hypotonia-spasticity-sleep disorder syndrome
Mondo ID	MONDO:0014210
OMIM	615493
Orphanet	356996
DOID	DOID:0081202
UMLS	C3809672
MedGen	816002
GARD	0017541
Is cancer (heuristic)	no

Also known as: intellectual disability, autosomal recessive 37 · intellectual disability, autosomal recessive type 37 · mental retardation, autosomal recessive 37 · mental retardation, autosomal recessive type 37 · mental retardation, autosomal recessive, 37 · MRT37

Data availability: 129 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › autosomal recessive syndromic intellectual disability › intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Related subtypes (6): Cohen syndrome, intellectual disability, autosomal recessive 53, short stature-brachydactyly-obesity-global developmental delay syndrome, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, intellectual developmental disorder with neuropsychiatric features, Al Kaissi syndrome

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

129 retrieved; paginated sample, class counts are floors:

74 uncertain significance, 26 conflicting classifications of pathogenicity, 14 benign, 5 likely pathogenic, 4 benign/likely benign, 4 pathogenic, 1 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4082355	NM_020987.5(ANK3):c.3589del (p.Ala1197fs)	ANK3	Pathogenic	criteria provided, single submitter
802576	NM_020987.5(ANK3):c.2659C>T (p.Gln887Ter)	ANK3	Pathogenic	criteria provided, single submitter
872695	NM_020987.5(ANK3):c.4365_4368del (p.Arg1456fs)	ANK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88648	NM_020987.5(ANK3):c.10995del (p.Thr3666fs)	ANK3	Pathogenic	no assertion criteria provided
918004	NM_020987.5(ANK3):c.11033del (p.Pro3678fs)	ANK3	Pathogenic	no assertion criteria provided
1050844	NM_020987.5(ANK3):c.2125C>T (p.Arg709Ter)	ANK3	Likely pathogenic	criteria provided, single submitter
2430260	NM_020987.5(ANK3):c.631C>T (p.Arg211Ter)	ANK3	Likely pathogenic	criteria provided, single submitter
3256665	NM_020987.5(ANK3):c.4867C>T (p.Arg1623Ter)	ANK3	Likely pathogenic	criteria provided, single submitter
3393908	NM_020987.5(ANK3):c.2706C>G (p.Tyr902Ter)	ANK3	Likely pathogenic	criteria provided, single submitter
4846809	NM_020987.5(ANK3):c.12910C>T (p.Gln4304Ter)	ANK3	Likely pathogenic	criteria provided, single submitter
1030746	NM_020987.5(ANK3):c.2467A>G (p.Met823Val)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1184343	NM_020987.5(ANK3):c.5183C>T (p.Ser1728Phe)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1338476	NM_020987.5(ANK3):c.5773GAG[1] (p.Glu1926del)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
162094	NM_020987.5(ANK3):c.2902G>C (p.Asp968His)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210142	NM_020987.5(ANK3):c.11825A>G (p.Lys3942Arg)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210160	NM_020987.5(ANK3):c.4400A>G (p.Lys1467Arg)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210161	NM_020987.5(ANK3):c.4465C>T (p.Pro1489Ser)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210168	NM_020987.5(ANK3):c.6555G>T (p.Gln2185His)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210171	NM_020987.5(ANK3):c.7469C>T (p.Pro2490Leu)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210176	NM_020987.5(ANK3):c.8534G>A (p.Gly2845Glu)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210177	NM_020987.5(ANK3):c.8573C>T (p.Ser2858Leu)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2192943	NM_020987.5(ANK3):c.8773T>G (p.Ser2925Ala)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3596352	NM_020987.5(ANK3):c.7516A>G (p.Ile2506Val)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
377484	NM_020987.5(ANK3):c.6695G>A (p.Arg2232Gln)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
377485	NM_020987.5(ANK3):c.9935C>T (p.Ala3312Val)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
423280	NM_020987.5(ANK3):c.148C>T (p.Arg50Ter)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
434154	NM_020987.5(ANK3):c.10688A>G (p.Glu3563Gly)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
434156	NM_020987.5(ANK3):c.9997A>T (p.Thr3333Ser)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
434160	NM_020987.5(ANK3):c.8592G>T (p.Lys2864Asn)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
434168	NM_020987.5(ANK3):c.5582C>T (p.Thr1861Met)	ANK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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
ANK3	Strong	Autosomal recessive	intellectual disability-hypotonia-spasticity-sleep disorder syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANK3	Orphanet:356996	ANK3-related intellectual disability-sleep disturbance syndrome
SHANK3	Orphanet:662169	Phelan-McDermid syndrome due to 22q13.3 deletion
SHANK3	Orphanet:662172	Phelan-McDermid syndrome due to SHANK3 mutation

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
ANK3	HGNC:494	ENSG00000151150	Q12955	Ankyrin-3	gencc,clinvar
SHANK3	HGNC:14294	ENSG00000251322	Q9BYB0	SH3 and multiple ankyrin repeat domains protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANK3	Ankyrin-3	Membrane-cytoskeleton linker.
SHANK3	SH3 and multiple ankyrin repeat domains protein 3	Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.0

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
Scaffold/PPI	2	17.3×	0.003

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ANK3	Scaffold/PPI	no		Death_dom, ZU5_dom, Ankyrin_rpt
SHANK3	Scaffold/PPI	no		SH3_domain, PDZ, SAM

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
Brodmann (1909) area 23	1
dorsal motor nucleus of vagus nerve	1
endothelial cell	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANK3	298	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, dorsal motor nucleus of vagus nerve
SHANK3	246	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANK3	6,145
SHANK3	3,702

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SHANK3	Q9BYB0	3
ANK3	Q12955	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interaction between L1 and Ankyrins	1	368.4×	0.021	ANK3
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	335.9×	0.021	ANK3
ER to Golgi Anterograde Transport	1	132.8×	0.023	ANK3
L1CAM interactions	1	120.2×	0.023	ANK3
COPI-mediated anterograde transport	1	109.8×	0.023	ANK3
Transport to the Golgi and subsequent modification	1	102.9×	0.023	ANK3
Asparagine N-linked glycosylation	1	60.1×	0.033	ANK3
Axon guidance	1	45.1×	0.036	ANK3
Nervous system development	1	42.9×	0.036	ANK3
Membrane Trafficking	1	37.1×	0.037	ANK3
Vesicle-mediated transport	1	34.8×	0.037	ANK3
Post-translational protein modification	1	19.2×	0.061	ANK3
Developmental Biology	1	14.5×	0.074	ANK3
Metabolism of proteins	1	12.4×	0.081	ANK3

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
positive regulation of cell communication by electrical coupling	1	4213.0×	0.003	ANK3
maintenance of protein location in plasma membrane	1	4213.0×	0.003	ANK3
guanylate kinase-associated protein clustering	1	4213.0×	0.003	SHANK3
positive regulation of membrane depolarization during cardiac muscle cell action potential	1	4213.0×	0.003	ANK3
positive regulation of synapse structural plasticity	1	2808.7×	0.003	SHANK3
striatal medium spiny neuron differentiation	1	2106.5×	0.003	SHANK3
membrane assembly	1	2106.5×	0.003	ANK3
negative regulation of cell volume	1	1685.2×	0.003	SHANK3
AMPA glutamate receptor clustering	1	1685.2×	0.003	SHANK3
NMDA glutamate receptor clustering	1	1685.2×	0.003	SHANK3
protein localization to axon	1	1685.2×	0.003	ANK3
regulation of long-term synaptic depression	1	1685.2×	0.003	SHANK3
negative regulation of actin filament bundle assembly	1	1404.3×	0.003	SHANK3
positive regulation of membrane potential	1	1404.3×	0.003	ANK3
negative regulation of delayed rectifier potassium channel activity	1	1404.3×	0.003	ANK3
positive regulation of homotypic cell-cell adhesion	1	1203.7×	0.003	ANK3
cellular response to magnesium ion	1	1203.7×	0.003	ANK3
vocal learning	1	1053.2×	0.003	SHANK3
magnesium ion homeostasis	1	936.2×	0.003	ANK3
regulation of potassium ion transport	1	936.2×	0.003	ANK3
positive regulation of long-term neuronal synaptic plasticity	1	936.2×	0.003	SHANK3
postsynaptic density assembly	1	936.2×	0.003	SHANK3
regulation of long-term synaptic potentiation	1	766.0×	0.003	SHANK3
positive regulation of glutamate receptor signaling pathway	1	766.0×	0.003	SHANK3
plasma membrane organization	1	443.5×	0.004	ANK3
dendritic spine morphogenesis	1	443.5×	0.004	SHANK3
vocalization behavior	1	443.5×	0.004	SHANK3
positive regulation of sodium ion transport	1	421.3×	0.004	ANK3
regulation of dendritic spine morphogenesis	1	421.3×	0.004	SHANK3
positive regulation of dendritic spine development	1	383.0×	0.005	SHANK3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
ANK3	0	0
SHANK3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
E	Difficult family or no structure, no drug	2	ANK3, SHANK3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ANK3	0	—
SHANK3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.