DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Weaver syndrome — screening already-approved drugs against its 4-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleWeaver syndrome maps to a 4-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 weaver 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
nuclear receptor binding SET domain protein 1 (NSD1) — NSD1 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 samdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3OOI · 1.75 Å · ligand S-ADENOSYLMETHIONINE (SAM). Experimental structure, not a prediction.
What the evidence adds up to
Weaver syndrome is a rare condition characterised by overgrowth, macrocephaly, accelerated osseous maturation, variable intellectual disability, and distinctive facial features including a broad forehead, hypertelorism, a long philtrum, micrognathia, and large ears. Two Japanese children, a three-year-old girl and a twenty-month-old boy, showed mild mental retardation, overgrowth with accelerated bone age, and unique behaviour with some social withdrawal. A separate report of a female patient described developmental delay, hypertonia, a hoarse voice, prominent finger pads, narrow hyperconvex nails, a small chest, a unilateral dislocated distal ulna, and abnormal thoracic vertebrae. Weaver syndrome carries an increased risk of malignancies, particularly neuroblastoma, leukaemia, and lymphoma.
Pathogenic variants in EZH2, a histone methyltransferase, were identified as a cause of Weaver syndrome in 2012. A 2016 report described a patient with a clinical diagnosis of Weaver syndrome whose exome was initially non-diagnostic; re-analysis after reports of EED-associated overgrowth revealed a likely pathogenic variant in EED, supporting locus heterogeneity. A 2023 case reported a male patient with a heterozygous likely pathogenic variant in EZH2 who had tall stature, distinctive facial features, mild developmental delay, hypoxic-ischaemic encephalopathy with periventricular leukomalacia on MRI, gingival hypertrophy, and early onset high hypermetropia.
In Brown Swiss cattle, a neurodegenerative disorder also called Weaver syndrome is characterised by progressive hind leg weakness and ataxia. Combined linkage and linkage disequilibrium mapping using SNP genotypes from 43 affected, 31 carrier, and 86 free animals identified a confidence interval on chromosome 4. Whole-genome sequence data from two official carriers and 1145 other bulls showed that only a non-synonymous SNP within the PNPLA8 gene was concordant with carrier status. Targeted genotyping in 2334 current Braunvieh animals suggested a Weaver allele frequency of 0.26%. The exact mechanisms underlying this syndrome remain to be uncovered.
No drug treatment for Weaver syndrome is described in these abstracts. What is missing is any clinical trial testing a therapy, any patient stratification beyond genetic diagnosis, and any funding directed toward pharmacological intervention for the human condition.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
American Journal of Medical Genetics Part A · 2016 · 60 citations
Novel <i>EED</i> mutation in patient with Weaver syndrome
Confirmation of a non-synonymous SNP in PNPLA8 as a candidate causal mutation for Weaver syndrome in Brown Swiss cattle
AbstractBACKGROUND: Bovine progressive degenerative myeloencephalopathy (Weaver syndrome) is a neurodegenerative disorder in Brown Swiss cattle that is characterized by progressive hind leg weakness and ataxia, while sensorium and spinal reflexes remain unaffected. Although the causal mutation has not been identified yet, an indirect genetic test based on six microsatellite markers and consequent exclusion of Weaver carriers from breeding have led to the complete absence of new cases for over two decades. Evaluation of disease status by imputation of 41 diagnostic single nucleotide polymorphisms (SNPs) and a common haplotype published in 2013 identified several suspected carriers in the current breeding population, which suggests a higher frequency of the Weaver allele than anticipated. In order to prevent the reemergence of the disease, this study aimed at mapping the gene that underlies Weaver syndrome and thus at providing the basis for direct genetic testing and monitoring of today's Braunvieh/Brown Swiss herds. RESULTS: Combined linkage/linkage disequilibrium mapping on Bos taurus chromosome (BTA) 4 based on Illumina Bovine SNP50 genotypes of 43 Weaver-affected, 31 Weaver carrier and 86 Weaver-free animals resulted in a maximum likelihood ratio test statistic value at position 49,812,384 bp. The confidence interval (0.853 Mb) determined by the 2-LOD drop-off method was contained within a 1.72-Mb segment of extended homozygosity. Exploitation of whole-genome sequence data from two official Weaver carriers and 1145 other bulls that were sequenced in Run4 of the 1000 bull genomes project showed that only a non-synonymous SNP (rs800397662) within the PNPLA8 gene at position 49,878,773 bp was concordant with the Weaver carrier status. Targeted SNP genotyping confirmed this SNP as a candidate causal mutation for Weaver syndrome. Genotyping for the candidate causal mutation in a random sample of 2334 current Braunvieh animals suggested a frequency of the Weaver allele of 0.26 %. CONCLUSIONS: Through combined use of exhaustive sequencing data and SNP genotyping results, we were able to provide evidence that supports the non-synonymous mutation at position 49,878,773 bp as the most likely causal mutation for Weaver syndrome. Further studies are needed to uncover the exact mechanisms that underlie this syndrome.
American Journal of Medical Genetics · 1991 · 12 citations
Weaver syndrome in two Japanese children
AbstractWe report on 2 Japanese patients (a 3-year-old girl and an 20-month-old boy) with the Weaver syndrome. The clinical manifestations are mild mental retardation, overgrowth with accelerated bone age, minor facial anomalies including broad forehead, mild hypertelorism, depressed nasal bridge, accentuated philtrum, micrognathia and large ears, and unique behavior characteristics with some social withdrawal. The nosology of the Weaver and Simpson-Golabi-Behmel syndromes is discussed.
Journal of Medical Genetics · 1987 · 11 citations · open access
A girl with the Weaver syndrome.
AbstractA female with the Weaver syndrome is reported. In addition to the characteristic manifestations of overgrowth and advanced bone age, the facies were typical, with a broad forehead, hypertelorism, a long philtrum, micrognathia, and large ears. Like most other patients with Weaver syndrome, she was developmentally delayed, hypertonic, and had a hoarse voice. Other clinical features included prominent finger pads, narrow hyperconvex nails, small and narrow chest, unilateral dislocated distal ulna, and abnormal thoracic vertebrae.
Molecular Syndromology · 2023 · 5 citations · open access
Expanding the Phenotypic and Genotypic Spectrum of Weaver Syndrome: A Missense Variant of the <i>EZH2</i> Gene
Abstract<b><i>Introduction:</i></b> Weaver syndrome (WS) is a rare autosomal dominant disorder characterized by distinctive facial features, pre- and post-natal overgrowth, macrocephaly, and variable developmental delay. The characteristic facial features are ocular hypertelorism, a broad forehead, almond-shaped palpebral fissures and, in early childhood, large, fleshy ears, a pointed “stuck-on” chin with horizontal skin creases, and retrognathia. Heterozygous pathogenic/likely pathogenic variants in the enhancer of zeste homolog 2 (<i>EZH2</i>) gene are responsible for WS. <b><i>Case Presentation:</i></b> Here, we report a male patient with a heterozygous likely pathogenic variant in EZH2 gene who has tall stature, distinctive facial features, mild development delay, hypoxic-ischemic encephalopathy with a MRI finding of periventricular leukomalacia, gingival hypertrophy, and early onset high hypermetropia. <b><i>Conclusion:</i></b> This case demonstrates the importance of reporting detailed molecular and clinical findings in patients to expand the genotypic and phenotypic findings of this rare syndrome.
Oxford University Press eBooks · 2019 · 2 citations
Weaver Syndrome and EZH2-Related Overgrowth Syndromes
AbstractComprehensive details on Weaver syndrome, one of the best recognized of the overgrowth syndromes, are presented in this chapter. The syndrome is characterized by overgrowth of prenatal onset, a distinctive craniofacial appearance, camptodactyly, widened metaphysis, accelerated bone age, and developmental delay. Like other overgrowth syndromes, Weaver syndrome is accompanied by an increased risk of malignancies, neuroblastoma, leukemia, and lymphoma in particular. The diagnosis relied on clinical evaluation alone until 2012 when the causative gene, <italic>EZH2</italic>, was discovered. The gene product joins with other related proteins to form a polycomb repressive complex that functions as an epigenetic signal that compacts chromatin and silences genes by histone modifications.
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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