DeCure for Intellectual disability, X-linked 99, syndromic, female-restricted
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for intellectual disability, X-linked 99, syndromic, female-restricted — 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 99, syndromic, female-restricted 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 99, syndromic, female-restricted 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
ubiquitin specific peptidase 9 X-linked (USP9X) — USP9X 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 unxdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5WCH · 2.5 Å · ligand UNKNOWN ATOM OR ION (UNX). Experimental structure, not a prediction.
What the evidence adds up to
Fragile X syndrome accounts for between one third and one half of all X-linked mental retardation, affects about 1 in 2500 males and a similar number of females, and is second in prevalence only to Down’s syndrome among the mental retardations. The 2025 case report describes a 3-year-old Brazilian female with a heterozygous pathogenic variant in the USP9X gene, c.7156C>T p.(Gln2386*), which creates a premature stop codon and causes loss of function through haploinsufficiency. This variant was not found in the Decipher or ClinVar databases. The patient had nonprogressive encephalopathy, neuropsychomotor developmental delay, corpus callosum agenesis, congenital hip dysplasia, and craniofacial anomalies. She was diagnosed with female-restricted X-linked syndromic intellectual developmental disorder-99, an ultrarare neurodevelopmental disorder characterised by developmental delays, behavioural alterations, and moderate-to-severe intellectual disability.
A separate 2022 case report describes a female with intellectual disability carrying a de novo heterozygous DDX3X mutation (c.694_711dup18) on the maternal X chromosome. Despite extreme skewing of X-chromosome inactivation that inactivated the mutant X chromosome, the mutant DDX3X allele still accounted for 30% of total DDX3X expression, and the patient remained symptomatic. The authors concluded that X-chromosome inactivation of the mutant allele was insufficient to reverse the phenotype of DDX3X-related neurodevelopmental disorder. DDX3X-related intellectual disability is more common in females and less common in males, who usually inherit the mutation from unaffected heterozygous mothers.
No treatment or intervention is described in any of these abstracts. The 2025 case report notes that documenting cases in different populations enriches knowledge of genetic variations and guides personalised treatments, but no specific therapy is tested or proposed. The 1994 abstract on fragile X syndrome states that the economic and social costs made determining its molecular basis a high priority, but no drug or clinical trial is mentioned. What remains missing are any clinical trials, any tested compounds, any patient stratification strategies beyond single-case reporting, and any funding directed toward therapeutic development for USP9X or DDX3X-related intellectual disability.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Fetal and Maternal Medicine Review · 1994 · 5 citations
Diagnosis of fragile X syndrome
AbstractFragile X syndrome accounts for between one third and one half of all X-linked mental retardation. It is the most common cause of familial intellectual handicap and is second in prevalence only to Down’s syndrome among the mental retardations. The syndrome is known to affect about 1 in 2500 males and a similar number of females. It has been detected in all ethnic groups with access to modern medicine. The economic and social costs of this disorder made the determination of its molecular basis a high priority.
Journal of Medical Case Reports · 2025 · 1 citations · open access
c.7156C > T p.(Gln2386*) variant causes loss-of-function of the USP9X gene in a female-restricted X-linked syndromic intellectual disability: a case report
AbstractBACKGROUND: Female-restricted X-linked syndromic intellectual developmental disorder-99 is an ultrarare neurodevelopmental disorder linked to X, manifesting in female individuals due to mutations in the USP9X gene. It is characterized by developmental delays, behavioral alterations, and moderate-to-severe intellectual disability. The USP9X gene plays critical roles in protein turnover and the regulation of essential pathways during neural development. This work describes the case of a Brazilian patient with female-restricted X-linked syndromic intellectual developmental disorder-99 with a variant not found in databases such as Decipher and ClinVar. Information was obtained from the Center for Rehabilitation and Readaptation Dr. Henrique Santillo electronic medical record system, and exams were conducted by partner laboratories of the Unified Health System. Documenting cases in different populations enriches the knowledge of genetic variations, guides personalized treatments, and expands the field of medical genetics, underscoring the importance of this study. CASE PRESENTATION: A 3-year-old female patient of Pardo admixed ethnicity from northern Brazil was referred to the Center for Rehabilitation and Readaptation Dr. Henrique Santillo for suspected genetic disorders. The child was born after an uneventful pregnancy but faced neonatal complications, including cardiopulmonary arrest and jaundice, requiring intensive care unit admission. She was diagnosed with nonprogressive encephalopathy and neuropsychomotor developmental delay. Additional tests revealed structural anomalies, such as corpus callosum agenesis and congenital hip dysplasia. Various genetic tests were performed, but only whole exome sequencing revealed a pathogenic variant in the USP9X gene, associated with female-restricted X-linked syndromic intellectual developmental disorder-99. CONCLUSION: We report the case of a child with a heterozygous pathogenic variant in the USP9X gene, located at Xp11.4 and presenting a wide range of phenotypes. The cytosine-to-thymine substitution resulted in a premature stop codon, causing female-restricted X-linked syndromic intellectual developmental disorder-99. The mutation leads to protein function loss due to haploinsufficiency, resulting in a dominant X-linked disorder. Loss-of-function mutations in the USP9X gene cause intellectual disability and congenital anomalies, with several craniofacial anomalies observed in the patient. Despite the de novo nature of most loss-of-function variants, maternal testing is crucial for estimating recurrence risk. Genetic investigation confirmed the variant's pathogenicity, highlighting diagnostic challenges and the importance of genetic research in understanding and managing female-restricted X-linked syndromic intellectual developmental disorder-99.
Image1_Case Report: De novo DDX3X mutation caused intellectual disability in a female with skewed X-chromosome inactivation on the mutant allele.TIF
Abstract<p>Skewed XCI plays an important role in the phenotypic heterogeneities of many X-linked disorders, even involving in diseases caused by XCI-escaping genes. DDX3X-related intellectual disability is more common in females and less common in males, who usually inherit from unaffected heterozygous mothers. As an X inactivation (XCI) escaping gene, the role of skewed XCI in the phenotype of DDX3X mutant female is unknown. Here we reported a DDX3X: c.694_711dup18 de novo heterozygous mutation in a female with intellectual disability on the maternal X chromosome on the basis of SNPs detected by PCR-sanger sequencing. AR assay revealed that the maternal mutant X chromosome was extremely inactivated in the proband. Using RNA sequencing and whole-exome sequencing, we quantified allelic read counts and allele-specific expression, and confirmed that the mutant X chromosome was inactive. Further, we verified that the mutant DDX3X allele had a lower expression level by RNA sequencing and RT-PCR, and the normal and mutated DDX3X expression accounted for respectively 70% and 30% of total. In conclusion, we found a symptomatic female with extreme skewing XCI in the DDX3X mutant allele. It was discovered that XCI in the mutant allele was insufficient to reverse the phenotype of DDX3X-related neurodevelopmental disorder. It contributed to a better understanding of the role of skewed XCI in phenotypic differences, which can aid in the genetic counseling and prenatal diagnosis of disorders in females with DDX3X defects.</p>
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.
