DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Coffin-Siris syndrome 1 — screening already-approved drugs against its 8-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 1 maps to a 8-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 1 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
SWI/SNF related BAF chromatin remodeling complex subunit C2 (SMARCC2) — SMARCC2 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 befdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7VDV · 3.4 Å · ligand BERYLLIUM TRIFLUORIDE ION (BEF). Experimental structure, not a prediction.
What the evidence adds up to
Coffin-Siris syndrome is a rare disorder caused by mutations in genes encoding components of the BAF complex, also known as the mammalian SWI/SNF-like complex. Mutations in the ARID1A gene account for approximately 13% of cases, with eight patients reported as of 2015. A 2015 case described a 20-month-old boy with a de novo missense mutation (p.Leu1713Pro) in a highly conserved leucine-rich motif of ARID1A; all previously reported ARID1A mutations associated with Coffin-Siris syndrome had been truncating and believed to be mosaic in lymphocytes. The authors noted that ARID1A heterozygous knockout mice are embryonic lethal, and that while cancer-associated ARID1A mutations are typically nonsense or frameshift, missense mutations in the same leucine-rich motif have been reported in tumours.
Two cases from 2022 with ARID1A mutations had dissimilar presentation and clinical course, illustrating the broad and non-specific clinical features of the syndrome. A 2023 report described two prenatal cases: one with a pathogenic SMARCB1 gene variant (c.1066_1067del, p.(Leu356AspfsTer4)) causing Coffin-Siris syndrome 3, and one with a novel ARID1A gene variant (c.1920+3_1920+6del) causing Coffin-Siris syndrome 2. The prenatal phenotype included 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 authors noted that the prenatal phenotype in Coffin-Siris syndrome has been rarely described.
No widely accepted diagnostic criteria exist for Coffin-Siris syndrome. 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. One 2019 case report described significant autistic features in a patient, but provided no quantitative data on response or survival. No drug treatments are mentioned in any of these abstracts.
What is still missing is any systematic trial of a therapeutic intervention, any patient stratification beyond genotype, and any funding for preclinical or clinical work aimed at modifying the course of the disorder. The natural history remains poorly quantified, and no biomarker for disease severity or progression has been established.
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 Case Reports · 2022 · 5 citations · open access
<scp>Coffin–Siris</scp> syndrome: Clinical description of two cases
AbstractCoffin-Siris syndrome is a rare disorder, which can be difficult to recognize. A broad spectrum of nonspecific clinical features is associated with Coffin-Siris syndrome, and the expression of these features is diverse. We describe two cases with Coffin-Siris syndrome with mutations in the ARID1A gene, with dissimilar presentation and clinical course.
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.
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.
