DYRK1A

Chr 21AD

dual specificity tyrosine phosphorylation regulated kinase 1A

Also known as: DYRK, DYRK1, HP86, MNB, MNBH, MRD7

NCBI Gene: 1859 ENSG00000157540 UniProt: Q13627 OMIM: 600855

This gene encodes a dual-specificity kinase that catalyzes autophosphorylation on serine/threonine and tyrosine residues and regulates cell proliferation and brain development. Mutations cause intellectual developmental disorder, autosomal dominant 7, predominantly through loss-of-function mechanisms. The gene shows extremely high constraint against loss-of-function variants (pLI 1.0, LOEUF 0.21), consistent with haploinsufficiency as the primary pathogenic mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the Dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. This member contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conservative 13-consecutive-histidine repeat. It catalyzes its autophosphorylation on serine/threonine and tyrosine residues. It may play a significant role in a signaling pathway regulating cell proliferation and may be involved in brain development. This gene is a homolog of Drosophila mnb (minibrain) gene and rat Dyrk gene. It is localized in the Down syndrome critical region of chromosome 21, and is considered to be a strong candidate gene for learning defects associated with Down syndrome. Alternative splicing of this gene generates several transcript variants differing from each other either in the 5' UTR or in the 3' coding region. These variants encode at least five different isoforms. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.211 OMIM phenotype

Clinical Summary— DYRK1A

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.21LOEUF

pLI 1.000

Z-score 5.11

OE 0.08 (0.04–0.21)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.34Z-score

OE missense 0.55 (0.50–0.61)

246 obs / 444.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.08 (0.04–0.21)

0≤0.351.4

Missense OE?0.55 (0.50–0.61)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 3 / 36.2Missense obs/exp: 246 / 444.4Syn Z: -1.48

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveDYRK1A-related intellectual developmental disorderLOFAD

This gene — mechanism propensity

0.2897th %ile

GOF

0.2895th %ile

LOF

0.84top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.21 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFImpaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References