DeCure for Autosomal dominant primary microcephaly
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for autosomal dominant primary microcephaly — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAutosomal dominant primary microcephaly maps to a 2-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 autosomal dominant primary microcephaly 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
lamin B1 (LMNB1) — LMNB1 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 7DTG · 3.6 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Thirteen patients from three families were described in 1983 with microcephaly and no neurological or dysmorphic findings, transmitted directly across generations including one male-to-male instance, consistent with autosomal dominant inheritance. A 1988 report of a single large family with 13 affected members across three generations confirmed autosomal dominant transmission with incomplete penetrance, including a skipped generation due to a non-manifesting heterozygote, and noted considerable variation in phenotypic expression. Both papers distinguished this uncomplicated form from other dominantly inherited microcephalies.
A 2025 study examined 418 individuals with microcephaly from 1050 exomes (312 trios, 106 proband-only samples), classifying them into primary microcephaly (PM) and secondary microcephaly (SM). Exome sequencing identified 142 causative and 12 candidate genes. Pathway analysis showed PM genes linked to early brain development and SM genes to later neuronal maturation. The PM group had a significantly higher proportion of autosomal recessive disorders and more severe microcephaly than the SM group. Females showed greater severity than males, attributed to differences in allele origin and X-chromosome inheritance patterns. Functional experiments using CRISPR-Cas9 knockout in neural progenitor cells and brain organoids demonstrated reduced proliferation for RTF1 and ASAP2.
A 2017 study reported that mutations in KIF14, encoding a kinesin-like protein, cause both autosomal recessive primary microcephaly (MCPH) and syndromic microcephaly. Most genes implicated in these conditions encode proteins involved in cell division, many localised to the centrosome.
What is still missing: no drug has been tested in any of these studies; there are no clinical trials, no repurposing screens, and no data on whether any existing compound could modify head growth or neurodevelopment in these genetic forms. The 2025 study does not report any therapeutic intervention. The autosomal dominant families described in 1983 and 1988 were not genetically characterised at the sequence level, so their molecular basis remains unknown. No patient stratification by specific gene mutation has been linked to any drug response. Funding for preclinical drug screening in microcephaly models, and trial designs that account for the genetic heterogeneity and incomplete penetrance of dominant forms, are absent.
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 · 1983 · 26 citations
Silent microcephaly: A distinct autosomal dominant trait
AbstractThirteen patients from three unrelated families were found to have microcephaly, without any neurological or dysmorphic manifestations. Autosomal dominant inheritance is concluded since the trait was transmitted directly in all three families, including one male-to-male instance. The recognition of this uncomplicated form of microcephaly as a Mendelian trait further extends its etiological heterogeneity.
AbstractA large family (13 affected members in three generations) is reported in which isolated microcephaly occurred without any other dysmorphic or neurological abnormalities. The family pedigree confirms the autosomal dominant mode of inheritance with incomplete penetrance, including one example of male to male transmission and the occurrence of a non-manifesting heterozygote resulting in a 'skipped generation'. There is considerable variation in the phenotypic expression of autosomal dominant microcephaly. This isolated (uncomplicated) type of microcephaly should be distinguished from other well defined, dominantly inherited forms of microcephaly.
Genome Medicine · 2025 · 4 citations · open access
Contribution of rare coding variants to microcephaly in individuals with neurodevelopmental disorders
AbstractBACKGROUND: Microcephaly, characterized by an abnormally small head size, frequently co-occurs with neurodevelopmental disorders (NDDs). While the genetic basis of NDDs has been widely investigated, the contribution of rare coding variants to microcephaly remains poorly understood. METHODS: We investigated the relationships between head circumference and rare coding variants in 418 individuals with microcephaly, analyzing data from 1050 exomes (312 trios and 106 proband-only samples). Participants were classified into primary microcephaly (PM) and secondary microcephaly (SM) groups, and their clinical and genetic characteristics were systematically assessed. The functional impact of high-priority candidate genes, RTF1 and ASAP2, was further validated using neural progenitor cells (NPCs) and human forebrain organoid models. RESULTS: Exome sequencing revealed 142 causative and 12 candidate genes associated with microcephaly. Pathway analyses indicated that PM genes are linked to early phases of brain development, whereas SM genes are more associated with later stages of neuronal maturation. In addition, the PM group had a significantly higher proportion of autosomal recessive disorders and exhibited more severe microcephaly than the SM group. Notably, females displayed greater microcephaly severity than males, primarily attributable to differences in the origin of the allele and inheritance patterns on the X chromosome. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of RTF1 and ASAP2 in brain development. CONCLUSIONS: This study sheds light on the complex genetic architecture of microcephaly, emphasizing the impact of rare coding variants on brain development and delineating distinct clinical and molecular profiles underlying PM and SM.
Mutations in KIF14, Encoding Kinesin-Like Protein KIF14, Cause Primary and Syndromic Microcephaly
AbstractPrimary microcephaly (small head) is a neurodevelopmental disorder characterized by a reduction in the size of the cerebral cortex accompanied with mild to moderate intellectual disability. This condition is observed either as an isolated form referred to as autosomal recessive primary microcephaly (MCPH) or in combination with additional features like growth retardation, renal and cranio-facial abnormalities or others subsumed under syndromic microcephaly. Both MCPH and syndromic microcephaly are heterogeneous disorders caused by mutations of many different genes. The majority of these genes encode proteins implicated in cell division and many of them have been localized at the centrosome.
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.
