DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for split hand-foot malformation 4 — 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 moduleSplit hand-foot malformation 4 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 split hand-foot malformation 4 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
tumor protein p63 (TP63) — TP63 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 7Z7E · 1.8 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
In a 2008 study of a large consanguineous kindred with autosomal recessive split-hand/foot malformation (SHFM), twelve affected members had central feet reductions with or without hand involvement, and one had a mild atypical phenotype. Homozygosity mapping identified a novel SHFM locus at 12q13.11-q13 with a maximum multipoint lod score of 5.47. A homozygous missense WNT10b mutation (p.R332W) was found in all affected individuals except the atypical case, and also in an asymptomatic female. The authors proposed that either a second locus contributes to the phenotype or a suppressor locus prevented trait manifestation in the non-penetrant female. Four of the five known SHFM loci were excluded, but in TP63 (SHFM4), the only known gene responsible for SHFM at that time, a rare insertion variant (rs34201045) at the alternate promoter used for transcription of the N-terminal-truncated p63 isotype was detected in most affected subjects. This was the first reported WNT10b mutation in limb development and the first recessive mutation in SHFM.
A 2019 review of nonsyndromic SHFM described it as a genetically heterogeneous disorder with variable expressivity and irregular genetic inheritance. The review provided an update of clinical and molecular aspects, listing major molecular genetic alterations reported to date. It noted that the condition is rare and highly complex, and aimed to assist in molecular diagnosis, recurrence risk assessment, and management planning.
A 2018 case report described a 94-year-old woman with deformities in all four limbs present from birth, suggestive of split hand/split foot malformation. She had no syndromic features and had lived without support or assistance for daily activities. She was a keen knitter and her son and three grandchildren were unaffected.
What is still missing is a clear understanding of the genetic and epigenetic modifiers that cause variable expressivity and non-penetrance, as seen in the 2008 kindred. No therapeutic trials exist for SHFM4, and no drug has been proposed or tested in any of these studies. The condition is managed by supportive care and genetic counselling, with no molecular treatment pathway available.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Molecular Genetics · 2008 · 81 citations
Homozygous WNT10b mutation and complex inheritance in Split-Hand/Foot Malformation
AbstractSplit-Hand/Foot Malformation (SHFM) is a complex limb malformation affecting the central rays of the autopod. We studied a large consanguineous kindred afflicted with autosomal recessive SHFM. Twelve affected members had central feet reductions with or without hand involvement while the remaining one had the mildest phenotype and atypical SHFM. We identified by homozygosity mapping a novel SHFM locus at 12q13.11-q13 with a maximum multipoint lod score of 5.47 and by subsequent candidate gene approach a homozygous missense WNT10b mutation (p.R332W) in all affected individuals but the atypical case plus in an asymptomatic female. We propose that either a second locus contributes to the manifestation of SHFM phenotype or a suppressor locus prevented trait manifestation in the non-penetrant female. We also investigated linkage to the five known SHFM loci. Four of the loci were excluded, while in TP63 [tumor protein p63 (SHFM4)], the only known gene responsible for SHFM, we detected in most affected subjects a rare insertion variant (rs34201045) at the alternate promoter used for transcription of the N-terminal-truncated p63 isotype. This is the first reported WNT10b mutation on the pathogenesis of limb development and recessive mutation in SHFM.
AbstractSplit-hand/foot malformation (SHFM) is a genetic limb anomaly disturbing the central rays of the autopod. SHFM is a genetically heterogeneous disorder with variable expressivity inherited as syndromic and nonsyndromic forms. We provide an update of the clinical and molecular aspects of nonsyndromic SHFM. This rare condition is highly complex due to the clinical variability and irregular genetic inheritance observed in the affected individuals. Nonsyndromic SHFM types have been reviewed in terms of major molecular genetic alterations reported to date. This updated overview will assist researchers, scientists, and clinicians in making an appropriate molecular diagnosis, providing an accurate recurrence risk assessment, and developing a management plan.
Journal of Orthopaedic Case Reports · 2023 · 2 citations · open access
A Rare Case Report of Split Hand and Foot Malformation
AbstractIntroduction: Authors report a rare case report about split hand and foot malformation (SHFM) also sometimes referred to as ectrodactyly. Case Report: The patient with hand and foot malformations presented to casualty. A 60-year-old male was brought with alleged history of road traffic accident with tenderness and deformity in left thigh. On further physical examination, a malformation was present in bilateral feet and right hand. Plain radiographs were taken after emergency primary management which revealed a fracture of shaft of femur of the left side and absence of 2nd and 3rd phalanges in bilateral feet and lobster claw like malformation in the right hand. The patient was further investigated and operated with femur interlocking nail and later discharged under stable condition. Screening for other congenital defects was done. Conclusion: Patients with SHFM should undergo screening for other congenital anomalies. Electrocardiogram, 2D ECHO, chest radiograph, and ultrasonography abdomen should be done. Genetic analysis ideally should be done to identify mutations involved. Surgical intervention is only required when patient demands improved function of limb.
Turkish Journal of Dermatology · 2015 · 1 citations · open access
Hand Foot Skin Reaction Associated with Sunitinib
AbstractSunitinib renal hcreli karsinom ve gastrointestinal stromal tmrl hastalarda yarar gsteren bir multikinaz inhibitrdr. Sunitinib pek ok kutanz toksisiteye yol amaktadr. El ayak deri reaksiyonu en karakteristik ve en sk grlen kutanz toksisitedir. Lezyonlar iyi snrl, zellikle basn alanlarna lokalize ve evresi eritem ile snrl sar, arl kallus benzeri hiperkeratoz ile karakterizedir. Elli drt yanda erkek hasta renal hcreli karsinom nedeniyle balanan 50 mg/gn oral sunitinib tedavisinin
BMJ Case Reports · 2018 · 0 citations · open access
Lady with ‘lobster claw’ feet
AbstractA 94-year-old woman admitted with confusion secondary to a urinary tract infection exhibited deformities in all four limbs that were present from birth. Her appearance was suggestive of split hand/split foot malformation a rare congenital condition that affects the central rays of the distal limb portion. She had no syndromic features and had lived without support or assistance of her daily activities. A keen knitter, she regularly knitted for her three grandchildren, all of which, along with her son, were unaffected by this condition.
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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