DeCure for DYRK1A-related intellectual disability syndrome
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for DYRK1A-related intellectual disability syndrome — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleDYRK1A-related intellectual disability syndrome maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for dyrk1a-related intellectual disability syndrome is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) — DYRK1A is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet 4pdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8T2H · 1.85 Å · ligand (4P)-4-{(3M)-3-[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}pyridin-2-amine (XIR). Experimental structure, not a prediction.
What the evidence adds up to
DYRK1A is a dosage-sensitive kinase gene. Overexpression in Down syndrome and loss-of-function mutations in DYRK1A-related intellectual disability syndrome both produce neurodevelopmental phenotypes, but the direction of the molecular defect is opposite. In Down syndrome, DYRK1A inhibitors have been proposed as a therapeutic strategy to reduce cognitive deficits in mouse models, though the exact molecular and cellular mechanisms targeted by inhibition remain unknown. For DYRK1A-related intellectual disability syndrome, which results from heterozygous loss-of-function variants or deletions, inhibition would be the wrong direction; the need is for increased DYRK1A function, but no such therapy is described in these abstracts.
The syndrome is rare and autosomal dominant, caused by de novo pathogenic variants or chromosomal rearrangements at the DYRK1A locus. In a 2020 report, two unrelated probands evaluated at the National Institutes of Health presented with primary microcephaly, absent or minimal speech, feeding difficulties, and cognitive impairment. Additional findings included enlarged cerebral subarachnoid spaces, retinal vascular tortuosity, and anomalous optic discs in one child, and ophthalmologic abnormalities with sensorineural hearing loss in the other. A 2023 study of 29 individuals with likely gene-disrupting DYRK1A variants confirmed autism spectrum disorder in 85% and intellectual disability in 89%. Their social communication profile was broadly similar to that of children with idiopathic autism and below-average nonverbal IQ, with particular difficulties in social reciprocity and nonverbal communication, plus high rates of sensory-seeking behaviours. A 2023 report of four patients of different ethnicity noted that ethnic variation in facial features may make the syndrome less recognisable.
A 2019 case report identified a de novo 1.9 Mb microdeletion at 21q22.12q22.13 that removed exon 1 of DYRK1A in a child with intellectual disability, developmental delay, and epilepsy, confirming DYRK1A as the candidate gene. In 2024, an induced pluripotent stem cell line was generated from a patient carrying a de novo missense mutation (c.1024G>T), with normal karyotype and three-germ-layer differentiation capacity, intended for disease mechanism studies and drug screening. No clinical trial of any drug for DYRK1A-related intellectual disability syndrome is reported in these abstracts. What is missing is a therapeutic strategy that increases DYRK1A function, funding for preclinical development, a suitable animal model for the haploinsufficiency state, and any clinical trial design that accounts for the syndrome’s rarity, variable expressivity, and the need for patient stratification by mutation type and developmental stage.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Frontiers in Behavioral Neuroscience · 2016 · 188 citations · open access
DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome
AbstractDown syndrome (DS) is one of the leading causes of intellectual disability, and patients with DS face various health issues, including learning and memory deficits, congenital heart disease, Alzheimer's disease (AD), leukemia, and cancer, leading to huge medical and social costs. Remarkable advances on DS research have been made in improving cognitive function in mouse models for future therapeutic approaches in patients. Among the different approaches, DYRK1A inhibitors have emerged as promising therapeutics to reduce DS cognitive deficits. DYRK1A is a dual-specificity kinase that is overexpressed in DS and plays a key role in neurogenesis, outgrowth of axons and dendrites, neuronal trafficking and aging. Its pivotal role in the DS phenotype makes it a prime target for the development of therapeutics. Recently, disruption of DYRK1A has been found in Autosomal Dominant Mental Retardation 7 (MRD7), resulting in severe mental deficiency. Recent advances in the development of kinase inhibitors are expected, in the near future, to remove DS from the list of incurable diseases, providing certain conditions such as drug dosage and correct timing for the optimum long-term treatment. In addition the exact molecular and cellular mechanisms that are targeted by the inhibition of DYRK1A are still to be discovered.
Molecular Genetics & Genomic Medicine · 2020 · 15 citations · open access
<i>DYRK1A</i> pathogenic variants in two patients with syndromic intellectual disability and a review of the literature
AbstractBACKGROUND: DYRK1A-Related Intellectual Disability Syndrome is a rare autosomal dominant condition characterized by intellectual disability, speech and language delays, microcephaly, facial dysmorphism, and feeding difficulties. Affected individuals represent simplex cases that result from de novo heterozygous pathogenic variants in DYRK1A (OMIM 614104), or chromosomal structural rearrangements involving the DYRK1A locus. Due to the rarity of DYRK1A-Related Intellectual Disability Syndrome, the spectrum of symptoms associated with this disease has not been completely defined. METHODS AND RESULTS: We present two unrelated cases of DYRK1A-Related Intellectual Disability Syndrome resulting from variants in DYRK1A. Both probands presented to the National Institutes of Health (NIH) with multiple dysmorphic facial features, primary microcephaly, absent or minimal speech, feeding difficulties, and cognitive impairment; features that have been previously reported in individuals with DYRK1A. During NIH evaluation, additional features of enlarged cerebral subarachnoid spaces, retinal vascular tortuosity, and bilateral anomalous large optic discs with increased cup-to-disc ratio were identified in the first proband and multiple ophthalmologic abnormalities and sensorineural hearing loss were identified in the second proband. CONCLUSION: We recommend that the workup of future of patients include a comprehensive eye exam. Early establishment of physical, occupational, and speech therapy may help in the management of ataxia, hypertonia, and speech impairments common in these patients.
Autism Research · 2023 · 11 citations · open access
Characterizing the autism spectrum phenotype in <scp><i>DYRK1A</i></scp>‐related syndrome
AbstractLikely gene-disrupting (LGD) variants in DYRK1A are causative of DYRK1A syndrome and associated with autism spectrum disorder (ASD) and intellectual disability (ID). While many individuals with DYRK1A syndrome are diagnosed with ASD, they may present with a unique profile of ASD traits. We present a comprehensive characterization of the ASD profile in children and young adults with LGDs in DYRK1A. Individuals with LGD variants in DYRK1A (n = 29) were compared to children who had ASD with no known genetic cause, either with low nonverbal IQ (n = 14) or average or above nonverbal IQ (n = 41). ASD was assessed using the ADOS-2, ADI-R, SRS-2, SCQ, and RBS-R. Quantitative score comparisons were conducted, as were qualitative analyses of clinicians' behavioral observations. Diagnosis of ASD was confirmed in 85% and ID was confirmed in 89% of participants with DYRK1A syndrome. Individuals with DYRK1A syndrome showed broadly similar social communication behaviors to children with idiopathic ASD and below-average nonverbal IQ, with specific challenges noted in social reciprocity and nonverbal communication. Children with DYRK1A syndrome also showed high rates of sensory-seeking behaviors. Phenotypic characterization of individuals with DYRK1A syndrome may provide additional information on mechanisms contributing to co-occurring ASD and ID and contribute to the identification of genetic predictors of specific ASD traits.
American Journal of Medical Genetics Part A · 2023 · 1 citations
Rock around <i>DYRK1A</i>: Ethnic diversity, clinical challenges
AbstractDYRK1A-related intellectual disability is a recently described syndrome characterized by microcephaly, global developmental delay, impaired speech development, and distinctive facial features, which let to define it as a recognizable syndrome. Here we report four new patients of different ethnicity, broadening the clinical phenotype of the condition and highlighting how ethnic influences in the facial appearance could make it less recognizable.
Stem Cell Research · 2024 · 1 citations · open access
Generation of a human induced pluripotent stem cell line (FDCHi012-A) from a patient with DYRK1A-related intellectual disability syndrome carrying DYRK1A mutation (c.1024G > T)
AbstractDYRK1A haploinsufficiency causes a neurodevelopmental syndrome termed DYRK1A-related intellectual disability syndrome which is associated with a range of symptoms including microcephaly, epileptic seizures, and autism spectrum disorder. Here, we generated an induced Pluripotent Stem Cell (iPSC) line with a de novo missense mutation (DYRKIA c.1024G > T) from the peripheral blood mononuclear cells of a patient with DYRK1A-related intellectual disability syndrome. This iPSC line showed normal karyotype, exhibited pluripotency, and has three embryonic germ layers differentiation capacity. This iPSC line will be of great use in investigating the disease mechanisms and drug screening for patients with DYRK1A-related intellectual disability syndrome.
[Identification of a de novo interstitial 21q22.12q22.13 deletion in a patient with intellectual disability].
AbstractOBJECTIVE: To explore the genetic basis of a child featuring intellectual disability, developmental delay and epilepsy. METHODS: Cytogenetic and molecular analysis including chromosomal karyotyping analysis, single nucleotide polymorphism array (SNP array) and qPCR were performed. RESULTS: The karyotype of the child was determined as 46, XX; SNP array: arr [19]21q22.12q22.13(36 860 195-38 801 482)×1 dn. A heterozygous 1.9 Mb microdeletion was detected at 21q22.12q22.13. qPCR has confirmed deletion of exon 1 of the DYRK1A gene, which has occurred de novo. CONCLUSION: A 21q22 deletion was diagnosed with multiple genetic methods. Genotype-phenotype correlation suggested DYRK1A to be a candidate for intellectual disability.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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