DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Coffin-Siris syndrome — screening already-approved drugs against its 12-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCoffin-Siris syndrome maps to a 12-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 coffin-siris 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
lysine demethylase 8 (KDM8) — KDM8 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 akgdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6F4N · 2.541 Å · ligand 2-OXOGLUTARIC ACID (AKG). Experimental structure, not a prediction.
What the evidence adds up to
Coffin-Siris syndrome is caused by mutations in genes encoding components of the BAF (mSWI/SNF) complex. Mutations in ARID1A account for approximately 13% of CSS cases, with eight patients reported as of 2015. A 2015 report described a 20-month-old boy with a de novo missense mutation (p. Leu1713Pro) in a conserved leucine-rich motif of ARID1A; all previously reported ARID1A mutations in CSS had been truncating and believed mosaic in lymphocytes. The authors noted that heterozygous ARID1A knockout mice are embryonic lethal, suggesting a vital role in development, and that missense mutations in the same leucine-rich motif have been reported in cancer. They offered three possibilities: the mutation sits in a critical developmental position, the effect is mild enough to avoid lethality, or the mutation causes moderate protein instability leading to a milder presentation. Functional studies were underway.
A 2023 report described two prenatal CSS cases with autosomal dominant pathogenic variants: a SMARCB1 gene deletion (c.1066_1067del, p.Leu356AspfsTer4) and a novel ARID1A gene splice-site deletion (c.1920+3_1920+6del). The prenatal phenotype is rarely described. The SMARCB1 case showed severely hypoplastic right ventricle with VSD, truncus arteriosus type III, persisting left superior and inferior caval vein, bilateral olfactory nerve aplasia, and hypoplastic thymus. The report included ultrasound, MRI, and post mortem pictures of the affected fetuses, widening the known phenotypic spectrum.
A 2019 case report described a patient with CSS and significant autistic features. No numbers or sample sizes were given in that abstract. The condition remains without widely accepted diagnostic criteria as of 2015. No drug treatment is mentioned in any of these abstracts. What is missing is any clinical trial, any pharmacological intervention, any patient stratification beyond genotype, and any funding for therapy development.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Clinical Genetics · 2015 · 1 citations
MG-102 Coffin-siris syndrome caused by a missense mutation in arid1a
Abstract<h3></h3> Coffin-Siris syndrome (CSS; OMIM <b><i>#</i></b>135900) is caused by mutations in genes encoding components of the BRMassociated factor (BAF) complex, also known as the mammalian SWItch/sucrose nonfermentable (mSWI/SNF)-like complex. Clinical features are variable and may include hypoplasia of the distal phalanx of the fifth digit, developmental delay, dysmorphic or coarse facial features, growth restriction, and malformations of the brain, heart, and other organs. No widely accepted diagnostic criteria yet exist. Mutations in the ARID1A gene account for approximately 13% of CSS cases with eight patients reported to date.<sup>1</sup> Here we describe a 20-month-old boy with clinical features consistent with CSS, including feeding difficulties, hypotonia, speech delay, CNS anomalies, hypoplastic 5th digits, thick lower lip vermillion, and hypertrichosis. Our patient was found to have a <i><i>de novo</i></i> missense mutation (p. Leu1713Pro) in a highly conserved amino acid residue located in one of the leucine-rich motifs of <i>ARID1A</i>. All reported mutations of <i>ARID1A</i> associated with CSS thus far have been truncating, and are believed to be mosaic in lymphocytes. <i>ARID1A </i>heterozygous knock out mice are embryonic lethal, suggesting a vital role in embryonic development. Notably, while mutations in <i>ARID1A</i> noted in cancer are typically nonsense or frameshift, missense mutations in this same leucine-rich motif have been reported. These findings suggest several possibilities including: 1. This mutation resides in a critical position key to the function of <i>ARID1A</i> in human development; 2. This effect may be mild or specific enough to be tolerated and not cause lethality; or 3. This mutation causes moderate instability of the protein leading to a milder clinical presentation. Studies are underway to determine the functional consequences of this missense mutation on <i>ARID1A</i> mRNA and protein production. <h3>Reference</h3> Kosho T, Okamoto N, Coffin-Siris Syndrome InternationalCollaborators. Genotype-phenotype correlation of Coffin-Siris syndrome causedby mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A. <i>Am J Med Genet C Semin Med Genet</i>. 2014;<b>166C</b>(3):262–75
Zenodo (CERN European Organization for Nuclear Research) · 2019 · 0 citations · open access
Coffin Siris Syndrome with Significant Autistic Features
AbstractAl-Mosawi AJ. Coffin Siris Syndrome with Significant Autistic Features. SunKrist Clinical and Medical Case Reports Journal.2019; 1(1): 1-3. Article No : scmcrj-v1-1002. Published Date: August 29, 2019. Doi: 10.5281/zenodo.3878428 https://casereports.sunkristpublishing.com/issue.php?id=MQ== https://casereports.sunkristpublishing.com/view_issue.php?id=Mw==
Sage Journals Data · 2023 · 0 citations · open access
Prenatal Coffin-Siris Syndrome: Expanding the Phenotypic and Genotypic Spectrum of the Disease
AbstractCoffin-Siris syndrome is an autosomal dominant disorder with neurological, cardiovascular, and gastrointestinal symptoms. Patients with Coffin-Siris syndrome typically have variable degree of developmental delay or intellectual disability, muscular hypotonia, dysmorphic facial features, sparse scalp hair, but otherwise hirsutism and fifth digit nail or distal phalanx hypoplasia or aplasia. Coffin-Siris syndrome is caused by pathogenic variants in 12 different genes including <i>SMARCB1</i> and <i>ARID1A</i>. Pathogenic <i>SMARCB1</i> gene variants cause Coffin-Siris syndrome 3 whereas pathogenic <i>ARID1A</i> gene variants cause Coffin-Siris syndrome 2. Here, we present two prenatal Coffin-Siris syndrome cases with autosomal dominant pathogenic variants: <i>SMARCB1</i> gene c.1066_1067del, p.(Leu356AspfsTer4) variant, and a novel <i>ARID1A</i> gene c.1920+3_1920+6del variant. The prenatal phenotype in Coffin-Siris syndrome has been rarely described. This article widens the phenotypic spectrum of prenatal Coffin-Siris syndrome with severely hypoplastic right ventricle with VSD and truncus arteriosus type III, persisting left superior and inferior caval vein, bilateral olfactory nerve aplasia, and hypoplastic thymus. A detailed clinical description of the patients with ultrasound, MRI, and <i>post mortem</i> pictures of the affected fetuses showing the wide phenotypic spectrum of the disease is presented.
Zenodo (CERN European Organization for Nuclear Research) · 2019 · 0 citations · open access
Coffin Siris Syndrome with Significant Autistic Features
AbstractAl-Mosawi AJ. Coffin Siris Syndrome with Significant Autistic Features. SunKrist Clinical and Medical Case Reports Journal.2019; 1(1): 1-3. Article No : scmcrj-v1-1002. Published Date: August 29, 2019. Doi: 10.5281/zenodo.3878428 https://casereports.sunkristpublishing.com/issue.php?id=MQ== https://casereports.sunkristpublishing.com/view_issue.php?id=Mw==
Journal of Pediatrics & Child Health Care · 2023 · 0 citations
Coffin-Siris Syndrome Presents with Novel ARID-2 Gene Mutation
AbstractCoffin-Siris Syndrome (CSS) is a rare genetic condition most commonly associated with ARID1A, ARID1B, ARID 2, SMARCA4, SMARCB1, DPF2, and SMARCE1 genetic mutations. The most common features of CSS are intellectual disabilities and facial abnormalities. We report a case of a 10-month-old infant who presented with craniosynostosis and developmental delays. Clinical improvement was observed after conservative therapy. This paper discusses the BAF gene family and how mutations in this gene family influence the development of children. The prognosis of CSS has also been discussed.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
