DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Timothy 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 moduleTimothy 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 timothy 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
calcium voltage-gated channel subunit alpha1 C (CACNA1C) — CACNA1C 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 2-butyl-1-benzofuran-3-yldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8FHS · 3.3 Å · ligand (2-butyl-1-benzofuran-3-yl){4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl}methanone (BBI). Experimental structure, not a prediction.
What the evidence adds up to
Timothy syndrome is caused by mutations in CACNA1C, a gene encoding a calcium channel. A 2014 study of 278 probands with long QT syndrome who were negative for other LQTS-related gene mutations found five novel CACNA1C mutations in seven individuals (2.5%). Functional analysis showed that the R858H mutant channel produced significantly larger peak calcium currents than wild-type, while the A582D mutant channel displayed significantly slower inactivation; both were gain-of-function effects. The authors concluded that CACNA1C mutations may cause QT prolongation or fatal arrhythmia even without the typical syndactyly of Timothy syndrome.
A 2018 case report described a five-year-old female with cutaneous syndactyly, developmental delay, and pulmonary hypertension who carried a de novo CACNA1C mutation (p.Arg1024Gly) but did not have QT prolongation. The authors stated this was the first reported patient with syndactyly and a CACNA1C mutation without QT prolongation, which had been considered an obligatory feature.
A 2024 natural history study surveyed parents of Timothy syndrome patients and grouped participants by genotype and initial diagnosis. The study found that long QT syndrome, neurodevelopmental impairments, hypoglycemia, and respiratory issues were frequently reported across all groups. Importantly, the incidence of these features was similar even among patients initially diagnosed with non-syndromic long QT type 8 (cardiac-only Timothy syndrome), suggesting that the non-syndromic classification may be incomplete. The authors noted that while cardiac arrhythmia has been well recognised, hypoglycemia and respiratory dysfunction also pose significant life-threatening risks.
A 2022 case report described a newborn with Timothy syndrome who had long QT syndrome and torsades de pointes, a life-threatening ventricular arrhythmia. The report focused on improving early diagnosis and management of LQTS type 8. What remains missing is prospective, longitudinal data that can confirm whether the cardiac-only label holds over time, and whether the non-cardiac risks (hypoglycaemia, respiratory dysfunction) are consistently present from infancy. No trial has tested any intervention specifically for the extra-cardiac features, and no stratification by specific CACNA1C variant has been used to guide management.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
EP Europace · 2014 · 95 citations · open access
Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes
AbstractAIMS: CACNA1C mutations have been reported to cause LQTS type 8 (LQT8; Timothy syndrome), which exhibits severe phenotypes, although the frequency of patients with LQT8 exhibiting only QT prolongation is unknown. This study aimed to elucidate the frequency of CACNA1C mutations in patients with long QT syndrome (LQTS), except those with Timothy syndrome and investigate phenotypic variants. METHODS AND RESULTS: CACNA1C gene screening was performed in 278 probands negative for LQTS-related gene mutations. Functional analysis of mutant channels using a whole-cell patch-clamp technique was also performed. Using genetic screening, we identified five novel CACNA1C mutations: P381S, M456I, A582D, R858H, and G1783C in seven (2.5%) unrelated probands. Seven mutation carriers showed alternative clinical phenotypes. Biophysical assay of CACNA1C mutations revealed that the peak calcium currents were significantly larger in R858H mutant channels than those of wild-type (WT). In contrast, A582D mutant channels displayed significantly slower inactivation compared with WT. The two mutant channels exerted different gain-of-function effects on calcium currents. CONCLUSION: In patients with LQTS, the frequency of CACNA1C mutations was higher than reported. Even without typical phenotypes of Timothy syndrome, CACNA1C mutations may cause QT prolongation and/or fatal arrhythmia attacks.
American Journal of Medical Genetics Part A · 2018 · 21 citations
Timothy syndrome‐like condition with syndactyly but without prolongation of the QT interval
AbstractTimothy syndrome is characterized by a unique combination of a prolongation of the corrected QT interval of the electrocardiogram and bilateral cutaneous syndactyly of the fingers and the toes and is caused by heterozygous mutations in CACNA1C, a gene encoding a calcium channel. After the discovery of the CACNA1C gene as the causative gene for Timothy syndrome, patients with CACNA1C mutations with QT prolongation but without syndactyly were described. Here, we report a 5-year-old female patient with cutaneous syndactyly, developmental delay, and pulmonary hypertension. Exome analysis showed a previously undescribed de novo heterozygous mutation in the CACNA1C gene, p.Arg1024Gly. To our knowledge, this patient is the first to exhibit syndactyly and to carry a CACNA1C mutation but to not have QT prolongation, which has long been considered an obligatory feature of Timothy syndrome.
Frontiers in Pediatrics · 2021 · 3 citations · open access
Case Report: Expanding the Phenotypic Spectrum of Timothy Syndrome Type 1: A Sporadic Case With a de novo CACNA1C Pathogenic Variant and Segmental Ileal Dilatation
AbstractBackground: Long QT syndactyly syndrome (long QT syndrome type 8), also known as Timothy Syndrome (TS) was first described in 1994 with still <50 case reported in the literature. The full spectrum of the syndrome is not yet known. Results: Here we report a girl who presented with new onset refractory seizures and an undiagnosed cause of intermittent abdominal distention. She also had syndactyly of her fingers and toes and was found to have prolonged QT. Upon further investigations she was found to have a de novo pathogenic variant in CACNA1C , along with Segmental Ileal Dilatation (SID), and subsequently diagnosed with Timothy syndrome. Conclusion: To our knowledge, the association of Timothy Syndrome with Segmental Ileal Dilatation, was not described before.
AbstractAbstract Background Timothy syndrome (OMIM #601005) is a rare disease caused by variants in the gene CACNA1C. Initially, Timothy syndrome was characterized by a cardiac presentation of long QT syndrome and syndactyly of the fingers and/or toes, all associated with the CACNA1C variant, Gly406Arg. However, subsequent identification of diverse variants in CACNA1C has expanded the clinical spectrum, revealing various cardiac and extra-cardiac manifestations. It remains underexplored whether individuals with the canonical Gly406Arg variants in mutually exclusive exon 8A (Timothy syndrome 1) or exon 8 (Timothy syndrome 2) exhibit overlapping symptoms. Moreover, case reports have indicated that some CACNA1C variants may produce a cardiac-selective form of Timothy syndrome often referred to as non-syndromic long QT type 8 or cardiac-only Timothy syndrome, however few reports follow up on these patients to confirm the cardiac selectivity of the phenotype over time. Methods A survey was administered to the parents of patients with Timothy syndrome, querying a broad range of symptoms and clinical features. Study participants were organized into 5 separate categories based on genotype and initial diagnosis, enabling comparison between groups of patients which have been described differentially in the literature. Results Our findings reveal that Timothy syndrome patients commonly exhibit both cardiac and extra-cardiac features, with long QT syndrome, neurodevelopmental impairments, hypoglycemia, and respiratory issues being frequently reported. Notably, the incidence of these features was similar across all patient categories, including those diagnosed with non-syndromic long QT type 8, suggesting that the ‘non-syndromic’ classification may be incomplete. Conclusions This study represents the first Natural History Study of Timothy syndrome, offering a comprehensive overview of the disease’s clinical manifestations. We demonstrate that both cardiac and extra-cardiac features are prevalent across all patient groups, underscoring the syndromic nature of CACNA1C variants. While the critical role of long QT syndrome and cardiac arrhythmias in Timothy syndrome has been well recognized, our findings indicate that hypoglycemia and respiratory dysfunction also pose significant life-threatening risks, emphasizing the need for comprehensive therapeutic management of affected individuals.
Research Square · 2022 · 0 citations · open access
Timothy Syndrome and Torsades De Pointes in a Newborn - Case Report
AbstractAbstract Timothy syndrome (TS) is a rare multisystem disease has a characterized association of long QT syndrome (LQTS) type-8 with the congenital cardiac and extracardiac malformations (neurological and dysmorphic facial features, syndactyly). It is caused by heterozygous mutations in the CACNA 1C gene, which participates in decoding the calcium channels. In this study, we describe a case of TS, which has systemic phenotypic characteristics associated with a long QT interval on the electrocardiogram.. The LQTS predisposes to a characteristic life-threatening ventricular arrhythmia known as Torsades de pointes or "twisting of the points". In this scenario, the authors describes the main clinical characteristics in a case of TS focusing on improve the ability of early diagnosis and better management of LTQS type-8.
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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