Intellectual disability, autosomal dominant 57

Summary

Intellectual disability, autosomal dominant 57 (MONDO:0054837) is a disease caused by TLK2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: TLK2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 93

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 57
Mondo ID	MONDO:0054837
OMIM	618050
DOID	DOID:0061031
UMLS	C4748003
MedGen	1648280
GARD	0025982
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, autosomal dominant 57 · intellectual disability, autosomal dominant 57 · mental retardation, autosomal dominant 57 · MRD57 · TLK2-Related Neurodevelopmental Disorder · TLK2-related neurodevelopmental disorder · TLK2-related syndrome

Data availability: 93 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 disability, autosomal dominant 57

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 62, intellectual developmental disorder, autosomal dominant 63, with macrocephaly, Coffin-Siris syndrome 6, 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

93 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 24 pathogenic, 20 likely pathogenic, 9 conflicting classifications of pathogenicity, 9 pathogenic/likely pathogenic, 2 likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
620261	NM_015570.4(AUTS2):c.376C>T (p.Arg126Ter)	AUTS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617933	NM_006852.6(TLK2):c.907C>T (p.Arg303Ter)	LOC126862611	Pathogenic	criteria provided, multiple submitters, no conflicts
807711	NM_006852.6(TLK2):c.968+1G>C	LOC126862611	Pathogenic	criteria provided, multiple submitters, no conflicts
828197	NM_006852.6(TLK2):c.968+1G>A	LOC126862611	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1194423	NM_006852.6(TLK2):c.1550+1G>A	TLK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1285495	NM_006852.6(TLK2):c.36del (p.Gln13fs)	TLK2	Pathogenic	criteria provided, single submitter
1699127	NM_006852.6(TLK2):c.1366A>T (p.Lys456Ter)	TLK2	Pathogenic	criteria provided, single submitter
1699234	NM_006852.6(TLK2):c.1121+1G>A	TLK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2692575	NM_006852.6(TLK2):c.267+1G>A	TLK2	Pathogenic	criteria provided, single submitter
3376137	NM_006852.6(TLK2):c.1415del (p.Gln472fs)	TLK2	Pathogenic	criteria provided, single submitter
3382792	NM_006852.6(TLK2):c.154-1G>A	TLK2	Pathogenic	criteria provided, single submitter
3544389	NM_006852.6(TLK2):c.1286+1G>A	TLK2	Pathogenic	criteria provided, single submitter
3572904	NM_006852.6(TLK2):c.1865del (p.Leu622fs)	TLK2	Pathogenic	criteria provided, single submitter
4056443	NM_006852.6(TLK2):c.2079+1G>A	TLK2	Pathogenic	criteria provided, single submitter
4528367	NM_006852.6(TLK2):c.865_866insTT (p.Ser289fs)	TLK2	Pathogenic	criteria provided, single submitter
4685552	NM_006852.6(TLK2):c.1187_1188+18del	TLK2	Pathogenic	criteria provided, single submitter
4813044	NM_006852.6(TLK2):c.736A>T (p.Arg246Ter)	TLK2	Pathogenic	criteria provided, single submitter
548933	NM_006852.6(TLK2):c.1720+1G>T	TLK2	Pathogenic	no assertion criteria provided
548935	NM_006852.6(TLK2):c.989C>A (p.Ser330Ter)	TLK2	Pathogenic	criteria provided, single submitter
548936	NM_006852.6(TLK2):c.1460+2T>G	TLK2	Pathogenic	no assertion criteria provided
617919	NM_006852.6(TLK2):c.784C>T (p.Arg262Ter)	TLK2	Pathogenic	criteria provided, multiple submitters, no conflicts
617921	NM_006852.6(TLK2):c.777C>A (p.Tyr259Ter)	TLK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617923	NM_006852.6(TLK2):c.202G>T (p.Glu68Ter)	TLK2	Pathogenic	criteria provided, single submitter
617928	NM_006852.6(TLK2):c.181C>T (p.Arg61Ter)	TLK2	Pathogenic	criteria provided, multiple submitters, no conflicts
617931	NM_006852.6(TLK2):c.1636C>T (p.Arg546Trp)	TLK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617935	NM_006852.6(TLK2):c.37C>T (p.Gln13Ter)	TLK2	Pathogenic	criteria provided, single submitter
617937	NM_006852.6(TLK2):c.1651C>T (p.Gln551Ter)	TLK2	Pathogenic	criteria provided, single submitter
620099	NM_006852.6(TLK2):c.364C>T (p.Arg122Ter)	TLK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
689792	NM_006852.6(TLK2):c.2107C>T (p.Arg703Ter)	TLK2	Pathogenic	criteria provided, multiple submitters, no conflicts
816982	NM_006852.6(TLK2):c.367C>T (p.Arg123Ter)	TLK2	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
TLK2	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 57	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AUTS2	Orphanet:352490	Autism spectrum disorder due to AUTS2 deficiency
AUTS2	Orphanet:641372	B-lymphoblastic leukemia/lymphoma with t(7;9)(q11.2;p13.2)

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TLK2	HGNC:11842	ENSG00000146872	Q86UE8	Serine/threonine-protein kinase tousled-like 2	gencc,clinvar
AUTS2	HGNC:14262	ENSG00000158321	Q8WXX7	Autism susceptibility gene 2 protein	clinvar
MRC2	HGNC:16875	ENSG00000011028	Q9UBG0	C-type mannose receptor 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TLK2	Serine/threonine-protein kinase tousled-like 2	Serine/threonine-protein kinase involved in the process of chromatin assembly and probably also DNA replication, transcription, repair, and chromosome segregation.
AUTS2	Autism susceptibility gene 2 protein	Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development.
MRC2	C-type mannose receptor 2	May play a role as endocytotic lectin receptor displaying calcium-dependent lectin activity.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TLK2	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
AUTS2	Other/Unknown	no		AUTS2
MRC2	Other/Unknown	no		FN_type2_dom, Ricin_B_lectin, C-type_lectin-like

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tibia	2
calcaneal tendon	1
colonic epithelium	1
sural nerve	1
cortical plate	1
ganglionic eminence	1
stromal cell of endometrium	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TLK2	185	tissue_specific	marker	calcaneal tendon, sural nerve, colonic epithelium
AUTS2	292	ubiquitous	marker	cortical plate, tibia, ganglionic eminence
MRC2	293	ubiquitous	marker	tendon of biceps brachii, stromal cell of endometrium, tibia

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TLK2	2,006
AUTS2	1,700
MRC2	998

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRC2	Q9UBG0	5
TLK2	Q86UE8	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AUTS2	Q8WXX7	41.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 3 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
Antigen processing-Cross presentation	1	158.6×	0.026	MRC2
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	150.3×	0.026	AUTS2
Cross-presentation of soluble exogenous antigens (endosomes)	1	126.9×	0.026	MRC2
Transcriptional regulation by RUNX1	1	73.2×	0.034	AUTS2
Class I MHC mediated antigen processing & presentation	1	35.0×	0.057	MRC2
Adaptive Immune System	1	14.9×	0.110	MRC2
RNA Polymerase II Transcription	1	11.3×	0.124	AUTS2
Gene expression (Transcription)	1	8.9×	0.136	AUTS2
Generic Transcription Pathway	1	7.5×	0.142	AUTS2
Immune System	1	6.5×	0.148	MRC2

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
nucleus localization	1	1404.3×	0.014	TLK2
dendrite extension	1	561.7×	0.014	AUTS2
regulation of chromatin organization	1	510.7×	0.014	TLK2
positive regulation of Rac protein signal transduction	1	216.1×	0.016	AUTS2
positive regulation of lamellipodium assembly	1	200.6×	0.016	AUTS2
cellular response to gamma radiation	1	200.6×	0.016	TLK2
peptidyl-serine phosphorylation	1	165.2×	0.016	TLK2
axon extension	1	165.2×	0.016	AUTS2
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	133.8×	0.016	TLK2
collagen catabolic process	1	130.6×	0.016	MRC2
negative regulation of autophagy	1	86.4×	0.022	TLK2
chromosome segregation	1	57.9×	0.030	TLK2
neuron migration	1	44.6×	0.036	AUTS2
osteoblast differentiation	1	40.4×	0.037	MRC2
chromatin organization	1	33.0×	0.041	TLK2
endocytosis	1	31.7×	0.041	MRC2
actin cytoskeleton organization	1	26.4×	0.046	AUTS2
protein phosphorylation	1	22.6×	0.051	TLK2
DNA damage response	1	17.8×	0.061	TLK2
intracellular signal transduction	1	12.7×	0.080	TLK2
positive regulation of transcription by RNA polymerase II	1	5.0×	0.188	AUTS2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
TLK2	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TLK2	11	4
AUTS2	0	0
MRC2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	TLK2
BOSUTINIB	4	TLK2
SUNITINIB	4	TLK2
ENZASTAURIN	3	TLK2
DOVITINIB	3	TLK2
LESTAURTINIB	3	TLK2
TOCERANIB	2	TLK2
SU-014813	2	TLK2
R-406	2	TLK2
KW-2449	1	TLK2
SU-9516	1	TLK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TLK2	185	Binding:185

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TLK2	185

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

11 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	TLK2
BOSUTINIB	4	TLK2
SUNITINIB	4	TLK2
ENZASTAURIN	3	TLK2
DOVITINIB	3	TLK2
LESTAURTINIB	3	TLK2
TOCERANIB	2	TLK2
SU-014813	2	TLK2
R-406	2	TLK2
KW-2449	1	TLK2
SU-9516	1	TLK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TLK2
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	AUTS2, MRC2

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)
AUTS2	0	—
MRC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.