intellectual disability syndrome due to a DYRK1A point mutation

Summary

intellectual disability syndrome due to a DYRK1A point mutation (MONDO:0018733) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 68

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		35	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

68 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0000504	Abnormality of vision	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000733	Abnormal repetitive mannerisms	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001518	Small for gestational age	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0003561	Birth length less than 3rd percentile	Frequent (30-79%)
HP:0009121	Abnormal axial skeleton morphology	Frequent (30-79%)
HP:0410263	Brain imaging abnormality	Frequent (30-79%)
HP:0000341	Narrow forehead	Occasional (5-29%)
HP:0000411	Protruding ear	Occasional (5-29%)
HP:0000426	Prominent nasal bridge	Occasional (5-29%)
HP:0000483	Astigmatism	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000490	Deeply set eye	Occasional (5-29%)
HP:0000540	Hypermetropia	Occasional (5-29%)
HP:0000543	Optic disc pallor	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000577	Exotropia	Occasional (5-29%)
HP:0000646	Amblyopia	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0001182	Tapered finger	Occasional (5-29%)
HP:0001773	Short foot	Occasional (5-29%)
HP:0001831	Short toe	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002363	Abnormal brainstem morphology	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002719	Recurrent infections	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0003319	Abnormality of the cervical spine	Occasional (5-29%)
HP:0006466	Ankle flexion contracture	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0007957	Corneal opacity	Occasional (5-29%)
HP:0011171	Simple febrile seizures	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability syndrome due to a DYRK1A point mutation
Mondo ID	MONDO:0018733
Orphanet	464311
UMLS	C5679991
MedGen	1826160
GARD	0021926
Is cancer (heuristic)	no

Also known as: DYRK1A-related intellectual disability syndrome due to a point mutation

Data availability: 1 ClinVar variant.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › DYRK1A-related intellectual disability syndrome › intellectual disability syndrome due to a DYRK1A point mutation

Related subtypes (1): DYRK1A-related intellectual disability syndrome due to 21q22.13q22.2 microdeletion

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

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
523623	NM_001347721.2(DYRK1A):c.1430G>A (p.Gly477Asp)	DYRK1A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DYRK1A	Orphanet:268261	DYRK1A-related intellectual disability syndrome due to 21q22.13q22.2 microdeletion
DYRK1A	Orphanet:464311	Intellectual disability syndrome due to a DYRK1A point mutation

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DYRK1A	HGNC:3091	ENSG00000157540	Q13627	Dual specificity tyrosine-phosphorylation-regulated kinase 1A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DYRK1A	Dual specificity tyrosine-phosphorylation-regulated kinase 1A	Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities.

Protein-family classification

Druggable: 1 · 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	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DYRK1A	Kinase	yes	2.7.12.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
amniotic fluid	1
biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DYRK1A	294	ubiquitous	marker	amniotic fluid, biceps brachii, Brodmann (1909) area 23

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DYRK1A	4,909

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYRK1A	Q13627	91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
G0 and Early G1	1	439.2×	0.002	DYRK1A

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of heterochromatin formation	1	8426.0×	8e-04	DYRK1A
regulation of amyloid-beta formation	1	8426.0×	8e-04	DYRK1A
regulation of neurofibrillary tangle assembly	1	5617.3×	8e-04	DYRK1A
negative regulation of microtubule polymerization	1	1296.3×	0.002	DYRK1A
negative regulation of DNA damage response, signal transduction by p53 class mediator	1	1123.5×	0.002	DYRK1A
positive regulation of RNA splicing	1	1053.2×	0.002	DYRK1A
negative regulation of mRNA splicing, via spliceosome	1	766.0×	0.003	DYRK1A
peptidyl-tyrosine phosphorylation	1	421.3×	0.004	DYRK1A
regulation of alternative mRNA splicing, via spliceosome	1	244.2×	0.006	DYRK1A
circadian rhythm	1	244.2×	0.006	DYRK1A
protein autophosphorylation	1	145.3×	0.009	DYRK1A
protein phosphorylation	1	68.0×	0.017	DYRK1A
nervous system development	1	45.9×	0.023	DYRK1A
positive regulation of DNA-templated transcription	1	27.9×	0.036	DYRK1A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
DYRK1A	NIRAPARIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DYRK1A	48	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIRAPARIB	4	DYRK1A
RUCAPARIB	4	DYRK1A
AFATINIB	4	DYRK1A
RUXOLITINIB	4	DYRK1A
PALBOCICLIB	4	DYRK1A
BELUMOSUDIL	4	DYRK1A
AFATINIB DIMALEATE	4	DYRK1A
ABEMACICLIB	4	DYRK1A
TOVORAFENIB	4	DYRK1A
SUNITINIB	4	DYRK1A
MIDOSTAURIN	4	DYRK1A
CURCUMIN	3	DYRK1A
CRENOLANIB	3	DYRK1A
EPIGALOCATECHIN GALLATE	3	DYRK1A
ENZASTAURIN	3	DYRK1A
DEFACTINIB	3	DYRK1A
CANERTINIB	3	DYRK1A
BARASERTIB	3	DYRK1A
ALVOCIDIB	3	DYRK1A
LORECIVIVINT	3	DYRK1A
LESTAURTINIB	3	DYRK1A
RUBOXISTAURIN	3	DYRK1A
SILMITASERTIB	2	DYRK1A
SELICICLIB	2	DYRK1A
CC-401	2	DYRK1A
SU-014813	2	DYRK1A
ZOTIRACICLIB	2	DYRK1A
TG100-115	2	DYRK1A
UPROSERTIB	2	DYRK1A
BGT-226 FREE BASE	2	DYRK1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DYRK1A	866	Binding:855, Functional:7, ADMET:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DYRK1A	2.7.12.1	dual-specificity kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
DYRK1A	866

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
NIRAPARIB	4	DYRK1A
RUCAPARIB	4	DYRK1A
AFATINIB	4	DYRK1A
RUXOLITINIB	4	DYRK1A
PALBOCICLIB	4	DYRK1A
BELUMOSUDIL	4	DYRK1A
AFATINIB DIMALEATE	4	DYRK1A
ABEMACICLIB	4	DYRK1A
TOVORAFENIB	4	DYRK1A
SUNITINIB	4	DYRK1A
MIDOSTAURIN	4	DYRK1A
CURCUMIN	3	DYRK1A
CRENOLANIB	3	DYRK1A
EPIGALOCATECHIN GALLATE	3	DYRK1A
ENZASTAURIN	3	DYRK1A
DEFACTINIB	3	DYRK1A
CANERTINIB	3	DYRK1A
BARASERTIB	3	DYRK1A
ALVOCIDIB	3	DYRK1A
LORECIVIVINT	3	DYRK1A
LESTAURTINIB	3	DYRK1A
RUBOXISTAURIN	3	DYRK1A
SILMITASERTIB	2	DYRK1A
SELICICLIB	2	DYRK1A
CC-401	2	DYRK1A
SU-014813	2	DYRK1A
ZOTIRACICLIB	2	DYRK1A
TG100-115	2	DYRK1A
UPROSERTIB	2	DYRK1A
BGT-226 FREE BASE	2	DYRK1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	DYRK1A
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	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.