DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for intellectual disability, X-linked 100 — 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 moduleIntellectual disability, X-linked 100 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 intellectual disability, x-linked 100 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.
What the evidence adds up to
X-linked intellectual disability accounts for a significant fraction of males with cognitive impairment, and mutations in over 100 X-chromosome genes have been identified. Deleterious mutations in roughly 10% of X-chromosome genes are implicated in causing XLID disorders in about 50% of families, with the remaining genes expected to be rare or private to individual families. At least 209 different XLID disorders have been described, including 143 syndromic forms. Fragile X syndrome is the most frequent and most studied XLID syndrome. It is now possible to identify 64% of the genetic defects in XLID families with obligate female carriers.
A deletion of the immunoglobulin domain of IL1RAPL1 results in nonsyndromic X-linked intellectual disability associated with behavioral problems and mild dysmorphism, with all published mutations predicting loss of function. A missense mutation A789V in IQSEC2 was identified in the MRX78 family, which includes six affected males and seven affected females. Functional assays showed that recombinant IQSEC2(A789V) could not catalyse GDP-GTP exchange on Arf6 as efficiently as wild-type IQSEC2. The Aristaless related homeobox (ARX) gene is one of the most frequently mutated XLID genes after FMR1 or MECP2, with more than 110 mutations reported; the phenotype always involves intellectual disability and often epilepsy, infantile spasms, hand dystonia, lissencephaly, autism or dysarthria.
In three families with idiopathic X-linked intellectual disability, targeted long read single molecule sequencing of over 1800 tandem repeats on the X chromosome achieved full length sequences for 88-93% of targets in male DNA samples. In one family, a repeat expansion co-occurred with down-regulation of the neighbouring MIR222 gene, which has previously been implicated in intellectual disability. The authors suggest tandem repeat mutations may be a hidden cause of X-linked intellectual disability. Expressive language sampling was evaluated as a procedure for generating outcome measures for treatment research in 106 individuals with fragile X syndrome between ages 6 and 23 years who had IQs within the range of intellectual disability.
What is still missing is the identification of the genetic defects in the remaining third of XLID families, adequate outcome measures for treatment trials beyond fragile X syndrome, and systematic investigation of tandem repeat expansions as a hidden cause across larger cohorts.
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 · 2011 · 41 citations
Deletion of the immunoglobulin domain of <i>IL1RAPL1</i> results in nonsyndromic X‐linked intellectual disability associated with behavioral problems and mild dysmorphism
AbstractX-Linked intellectual disability accounts for a significant fraction of males with cognitive impairment. Many of these males present with a non-syndromic phenotype and presently mutations in 17 X-linked genes are associated with these patients. Mutations in IL1RAPL1 have been found in multiple families with non-syndromic X-linked intellectual disability. All of the published mutations predict loss of function of the protein. We have identified an additional two families with deletions of a portion of the gene that give rise to cognitive impairment, as well as some behavioral problems and mild dysmorphism. Our clinical findings better delineate the phenotypic spectrum associated with IL1RAPL1 mutations.
Frontiers in Molecular Neuroscience · 2016 · 27 citations · open access
Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family
AbstractDisease gene discovery in neurodevelopmental disorders, including X-linked intellectual disability (XLID) has recently been accelerated by next-generation DNA sequencing approaches. To date, more than 100 human X chromosome genes involved in neuronal signaling pathways and networks implicated in cognitive function have been identified. Despite these advances, the mutations underlying disease in a large number of XLID families remained unresolved. We report the resolution of MRX78, a large family with six affected males and seven affected females, showing X-linked inheritance. Although a previous linkage study had mapped the locus to the short arm of chromosome X (Xp11.4-p11.23), this region contained too many candidate genes to be analyzed using conventional approaches. However, our X-chromosome exome resequencing, bioinformatics analysis and inheritance testing revealed a missense mutation (c.C2366T, p.A789V) in IQSEC2, encoding a neuronal GDP-GTP exchange factor for Arf family GTPases (ArfGEF) previously implicated in XLID. Molecular modeling of IQSEC2 revealed that the A789V substitution results in the insertion of a larger side-chain into a hydrophobic pocket in the catalytic Sec7 domain of IQSEC2. The A789V change is predicted to result in numerous clashes with adjacent amino acids and disruption of local folding of the Sec7 domain. Consistent with this finding, functional assays revealed that recombinant IQSEC2(A789V) was not able to catalyze GDP-GTP exchange on Arf6 as efficiently as wild-type IQSEC2. Taken together, these results strongly suggest that the A789V mutation in IQSEC2 is the underlying cause of XLID in the MRX78 family.
BMC Medical Genomics · 2018 · 6 citations · open access
Mapping the landscape of tandem repeat variability by targeted long read single molecule sequencing in familial X-linked intellectual disability
AbstractBACKGROUND: The etiology of more than half of all patients with X-linked intellectual disability remains elusive, despite array-based comparative genomic hybridization, whole exome or genome sequencing. Since short read massive parallel sequencing approaches do not allow the detection of larger tandem repeat expansions, we hypothesized that such expansions could be a hidden cause of X-linked intellectual disability. METHODS: We selectively captured over 1800 tandem repeats on the X chromosome and characterized them by long read single molecule sequencing in 3 families with idiopathic X-linked intellectual disability. RESULTS: In male DNA samples, full tandem repeat length sequences were obtained for 88-93% of the targets and up to 99.6% of the repeats with a moderate guanine-cytosine content. Read length and analysis pipeline allow to detect cases of > 900 bp tandem repeat expansion. In one family, one repeat expansion co-occurs with down-regulation of the neighboring MIR222 gene. This gene has previously been implicated in intellectual disability and is apparently linked to FMR1 and NEFH overexpression associated with neurological disorders. CONCLUSIONS: This study demonstrates the power of single molecule sequencing to measure tandem repeat lengths and detect expansions, and suggests that tandem repeat mutations may be a hidden cause of X-linked intellectual disability.
Oxford University Press eBooks · 2016 · 3 citations
Developmental Abnormalities Due to Mutations in the Aristaless-Related Homeobox Gene
AbstractAbstract Intellectual disability is a broad spectrum of neurodevelopmental disorders of the brain that combined affect approximately one in 50 individuals worldwide. X-linked intellectual disabilities represent a group of disorders where mutations arise on the X-chromosome. XLID is clinically complex and genetically heterogeneous. In excess of 100 genes are currently known. One of the most frequently mutated XLID genes (after e.g. FMR1 or MECP2) is the Aristaless related homeobox (ARX) gene. More than 110 mutations have been reported in ARX. The phenotype always involves intellectual disability and often also epilepsy, infantile spasms, hand dystonia, lissencephaly, autism or dysarthria. This chapter summarizes currently known mutations in ARX and their clinical manifestations and explores what is known about the underlying molecular and cellular mechanisms.
Expressive language sampling as a source of outcome measures for treatment studies in fragile X syndrome: feasibility, practice effects, test-retest reliability, and construct validity
AbstractAbstract Background The evaluation of treatment efficacy for individuals with fragile X syndrome (FXS) or intellectual disability (ID) more generally has been hampered by the lack of adequate outcome measures. We evaluated expressive language sampling (ELS) as a procedure for generating outcome measures for treatment research in FXS. We addressed: (a) feasibility, (b) practice effects over two administrations, (c) test-retest reliability over the repeated administrations, and (d) construct validity. We addressed these issues for the full sample as well as for subgroups defined by age, IQ, and ASD status. Methods Participants were 106 individuals with FXS between ages 6 and 23 years who had IQs within the range of intellectual disability (IQ
Encyclopedia of Life Sciences · 2017 · 0 citations
Genetics of <scp>X</scp> ‐Linked Intellectual Disability
AbstractAbstract X‐linked intellectual disability (XLID), formerly called mental retardation , refers to a group of inherited disorders characterised by varying degrees of intellectual disability caused by mutations in various genes present on the X‐chromosome. Deleterious mutations in ∼ 10% of X‐chromosome X genes are implicated in causing XLID disorders in ∼ 50% of families. The remaining XLID genes are expected to be rare and even private to individual families. Historically, XLID is divided into syndromic (IDXS) and nonsyndromic (IDX). At least 209 different XLID disorders have been described including 143 forms of syndromic mental retardation. Fragile X syndrome is the most frequent syndrome and most studied XLID syndrome. It is now possible to identify 64% of the genetic defects in XLID families with obligate female carriers. Most of the mutated genes in XLID are thought to influence development, cell migration, formation and maintenance of neural networks and cell‐to‐cell communication in the brain. Thus, the diagnosis of intellectual disability in a child has an enormous impact in most affected families. Genetic counselling is strongly recommended to family members. Key Concepts X‐linked intellectual disability (XLID) is a very heterogeneous set of conditions responsible for a large proportion of inherited mental retardation. XLID can be divided into syndromic (MRID) and nonsyndromic (IDX). Genes involved in XLID influence development, cell migration, formation and maintenance of neural networks and cell‐to‐cell communication in the brain. Intellectual disability phenotype can emerge as the final common pathway for many different types of abnormal cellular processing. Genetic counselling is an important part in general management in the case of intellectual disability.
Greater South Information System · 2017 · 0 citations · open access
Fragile X Syndrome: Prevalence, Treatment, and Prevention in China
AbstractFragile X syndrome (FXS) is the most common inherited cause of intellectual disability (ID) and the leading monogenic cause of autism spectrum disorder (ASD). Although FXS has been studied for several decades, there is relatively little basic science or clinical research being performed on FXS in China. Indeed, there is a large gap between China and Western countries in the FXS field. China has a potentially large number of FXS patients. However, many of them are under-diagnosed or even misdiagnosed, and treatments are not always administered in the Chinese population. This review discusses the prevalence, treatment, and prevention of FXS in China to facilitate an understanding of this disease in the Chinese population.
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.
