DYRK1A

Gene Facts

• HGNC Symbol: DYRK1A (HGNC:3091)
• HGNC Name: dual specificity tyrosine phosphorylation regulated kinase 1A
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: DYRK1, DYRK, MNBH
• Alias symbols: No aliases found
• %HI: 3.69
• pLI: 1
• LOEUF: 0.17
• Cytoband: 21q22.13
• Genomic Coordinates:

  GRCh37/hg19:	chr21:38737875-38898660
  GRCh38/hg38:	chr21:37365573-37526358

• MANE Select Transcript: NM_001347721.2 ENST00000647188.2
• Function: Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities (PubMed:21127067, PubMed:8769099, PubMed:30773093, PubMed:20981014, PubMed:23665168). Exhibits a substrate preference for proline at position P+1 and arginine at position P-3 (PubMed:23665168). Plays an important role in double- strand breaks (DSBs) repair following DNA damage (PubMed:31024071). Mechanistically, phosphorylates RNF169 and increases its ability to block accumulation of TP53BP1 at the DSB s... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-36235
• ClinGen Curation ID: CCID:007045
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 12/16/2020

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• DYRK1A-related intellectual disability syndrome

HI Evidence

• PUBMED: 22495309
  O'Roak et al. (2012) performed WES on 189 trios from the Simons Simpex Collection. They found a de novo splice site mutation in DYRK1A in a female with autism and microcephaly.
• PUBMED: 21294719
  van Bon et al. (2011) analyzed 3009 patients with ID for CNVs in DYRK1A using Affy 250K SNP array data. Patients with pathogenic CNVs greater than 150 kb were excluded from the study. One deletion was identified and confirmed by qPCR and a NimbleGen custom array. The deletion was 52 kb, removing the last 3 exons of DYRK1A (no other genes are involved), and de novo. The proband had ID, microcephaly, and "anxious autistic behavior".
• PUBMED: 25944381
  Ji et al (2015) identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs.

• HI Evidence Comments: Variants in this gene are associated with autosomal dominant intellectual disability and microcephaly. Additional literature: PMID: 23099646 Courcet et al (2012) identified a de novo frameshift mutation (c.290_291delCT; p.Ser97Cysfs*98) in a patient with growth retardation, primary severe microcephaly, delayed language, ID, and seizures. Though the following was not counted as evidence in this review, Moller et al. (2008) (PMID: 18405873) identified two unrelated patients with similar phenotypes with de novo balanced translocations that disrupted DYRK1A. The first patient was 24 months at time of the report and had microcephaly, DD, feeding problems, febrile convulsions, and "hand stereotypes". For this patient, a de novo balanced tranlocation t(9;21)(p12;q22) was identified with the chr9 breakpoint in a seg dup region with no genes. The chr21 breakpoint occurred within the second intron of DYRK1A as determined by FISH and tiling path BAC array. The second patient had severe ID, microcephaly, feeding problems, and febrile convulsions. She had a de novo balanced translocation t(2;21)(q22;q22) with the chr2 breakpoint in LRP1B and the chr21 breakpoint in DYRK1A.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: This gene is located in the Down Syndrome Critical Region. Isolated, single gene duplication of DYRK1A has not been reported in the medical literature. Note: PMID 17145134: Dowjat et al. (2007) analyzed DYRK1A protein in 17 DS brain tissues vs 12 control brain tissues. They report a ~1.5 fold increase in protein in the DS samples as compared to the controls.