DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for TWIST1-related craniosynostosis — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleTWIST1-related craniosynostosis maps to a 3-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 twist1-related craniosynostosis 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 acetyltransferase 6B (KAT6B) — KAT6B 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6OIE · 2.075 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
In 2001, a survey of the TWIST gene in craniosynostosis patients found, alongside 11 novel and one known pathogenic mutation, several individuals with rearrangements of the glycine-rich region — deletions of 18 nucleotides or insertions of three, 15, or 21 nucleotides. None of these rearrangements was consistently associated with clinical disease, and the authors concluded they are at most weakly pathogenic. The glycine stretch may serve as a flexible linker between functional domains of the TWIST protein and may be subject to reduced evolutionary constraint.
A 2007 study of 164 infants with isolated single-suture craniosynostosis identified two patients with novel TWIST Box mutations: one with isolated sagittal synostosis and one with isolated coronal synostosis. Prior to that study, no TWIST1 mutations had been published in the anti-osteogenic C-terminal TWIST Box, which binds and inhibits RUNX2 transactivation. The authors argued the mutations were pathogenic because a mouse with a mutation of the same residue developed sagittal synostosis, the mutation precluded TWIST1 interaction with RUNX2, the substitutions were nonconservative in highly conserved residues, and control chromosomes lacked such alterations. They suggested genetic testing of patients with isolated sagittal or coronal synostosis should include TWIST1 mutational analysis.
A 2013 cohort of 630 Australian and New Zealand patients with craniosynostosis found that 231 had one of 80 distinct mutations (36%) in FGFR1, FGFR2, FGFR3, or TWIST1. Among the 80 mutations, 17 were novel. Dysmorphic features consistent with known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. There was a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. No drug treatment was tested or proposed in that study.
A 2015 review noted that genetic mutations have been identified in FGFRs, TWIST1, BMP, and RUNX2, and that greater understanding of these pathways has led to development of innovative approaches for applying medical therapies to craniosynostosis, in particular by maintaining suture patency. The review highlighted recent developments in molecular craniosynostosis research with the hope of identifying targets for medical therapies that might augment surgical results. No specific drug, clinical trial, or patient outcome data were reported.
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 · 2007 · 109 citations
Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations
AbstractCraniosynostosis, the premature fusion of one or more cranial sutures, affects 1 in 2,500 live births. Isolated single-suture fusion is most prevalent, with sagittal synostosis occurring in 1/5,000 live births. The etiology of isolated (nonsyndromic) single-suture craniosynostosis is largely unknown. In syndromic craniosynostosis, there is a highly nonrandom pattern of causative autosomal dominant mutations involving TWIST1 and fibroblast growth factor receptors (FGFRs). Prior to our study, there were no published TWIST1 mutations in the anti-osteogenic C-terminus, recently coined the TWIST Box, which binds and inhibits RUNX2 transactivation. RUNX2 is the principal master switch for osteogenesis. We performed mutational analysis on 164 infants with isolated, single-suture craniosynostosis for mutations in TWIST1, the IgIIIa exon of FGFR1, the IgIIIa and IgIIIc exons of FGFR2, and the Pro250Arg site of FGFR3. We identified two patients with novel TWIST Box mutations: one with isolated sagittal synostosis and one with isolated coronal synostosis. Kress et al. [2006] reported a TWIST Box "nondisease-causing polymorphism" in a patient with isolated sagittal synostosis. However, compelling evidence suggests that their and our sequence alterations are pathogenic: (1) a mouse with a mutation of the same residue as our sagittal synostosis patient developed sagittal synostosis, (2) mutation of the same residue precluded TWIST1 interaction with RUNX2, (3) each mutation involved nonconservative amino acid substitutions in highly conserved residues across species, and (4) control chromosomes lacked TWIST Box sequence alterations. We suggest that genetic testing of patients with isolated sagittal or coronal synostosis should include TWIST1 mutational analysis.
American Journal of Medical Genetics Part C Seminars in Medical Genetics · 2013 · 51 citations · open access
Genotype and clinical care correlations in craniosynostosis: Findings from a cohort of 630 Australian and New Zealand patients
AbstractCraniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis.
A survey ofTWIST for mutations in craniosynostosis reveals a variable length polyglycine tract in asymptomatic individuals
AbstractThe human TWIST gene encodes a 202 amino acid transcription factor characterized by a highly conserved basic-helix-loop-helix motif in the C-terminal half, and a less conserved N-terminal half that has binding activity toward the histone acetyltransferase p300. Between these domains is a repeat region of unknown function that encodes the glycine-rich sequence (Gly)5Ala(Gly)5. Heterozygous mutations of TWIST were previously described in Saethre-Chotzen craniosynostosis syndrome [El Ghouzzi et al., 1997; Howard et al., 1997]. During a search for TWIST mutations in patients with craniosynostosis, we identified, in addition to 11 novel and one previously described bona fide mutations, several individuals with rearrangements of the glycine-rich region, involving either deletion of 18 nucleotides or insertion of three, 15, or 21 nucleotides. None of these rearrangements was consistently associated with clinical disease and we conclude that they are at most weakly pathogenic. The glycine stretch may serve as a flexible linker between the functional domains of the TWIST protein, and as such may be subject to reduced evolutionary constraint.
Neurosurgical FOCUS · 2015 · 17 citations · open access
Insights into the development of molecular therapies for craniosynostosis
AbstractFor the past 2 decades, clinical and basic science researchers have gained significant insights into the molecular and genetic pathways associated with common forms of craniosynostosis. This has led to invaluable information for families and physicians in their attempts to understand the heterogeneity of craniosynostosis. Genetic mutations have been identified in the fibroblast growth factor receptors (FGFRs) as well as in other targets, including TWIST1, BMP, and RUNX2. Greater understanding of these and other pathways has led to the development of innovative approaches for applying medical therapies to the treatment of craniosynostosis, in particular by maintaining suture patency. In this article, the authors discuss the molecular pathophysiological mechanisms underlying various forms of craniosynostosis. They also highlight recent developments in the field of molecular craniosynostosis research with the hope of identifying targets for medical therapies that might augment the results of surgical intervention.
Journal of Pediatric Genetics · 2023 · 1 citations · open access
TWIST1 Gene Variants Cause Craniosynostosis with Limb Abnormalities in Asian Patients
AbstractAbstract The TWIST1 gene codes for a highly conserved transcription factor in a basic helix–loop–helix transcription factors family. The pattern of inheritance is autosomal dominant in Saethre–Chotzen syndrome, Robinow–Sorauf syndrome, and Sweeney–Cox syndrome. Major features of these syndromes include coronal synostosis, vision problems, and deafness, and facial features include hypertelorism, low-set ears, arched eyebrows, beaked nose, maxillary hypoplasia, and other dysmorphisms including broad great toes, clinodactyly, brachydactyly, and cutaneous syndactyly. TWIST1 (bHLH) transcription factor regulates the formation of head and limbs in the embryo. We describe three families affected with craniosynostosis in whom a sporadic TWIST1 variant was identified on whole exome sequencing, chromosomal microarray, and Sanger sequencing.
Clinical Chemistry and Laboratory Medicine (CCLM) · 2014 · 1 citations
Reply to the article entitled “Identification of an 18 bp deletion in the TWIST1 gene by CO-amplification at lower denaturation temperature-PCR (COLD-PCR) for non-invasive prenatal diagnosis of craniosynostosis: first case report” by Galbiati et al., Clin Chem Lab Med 2014;52(4):505–9
AbstractArticle Reply to the article entitled “Identification of an 18 bp deletion in the TWIST1 gene by CO-amplification at lower denaturation temperature-PCR (COLD-PCR) for non-invasive prenatal diagnosis of craniosynostosis: first case report” by Galbiati et al., Clin Chem Lab Med 2014;52(4):505–9 was published on July 1, 2014 in the journal Clinical Chemistry and Laboratory Medicine (CCLM) (volume 52, issue 7).
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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