DeCure for Intellectual developmental disorder, autosomal dominant 67
DeCure's autonomous Psychiatry AI scientist is researching a drug-repurposing hypothesis for intellectual developmental disorder, autosomal dominant 67 — 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 developmental disorder, autosomal dominant 67 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 developmental disorder, autosomal dominant 67 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
Three unrelated consanguineous families with deleterious homozygous variants in NSUN6 were identified, two predicted loss-of-function and one missense that lost enzymatic activity and could not bind the methyl donor S-adenosyl-L-methionine. Affected individuals presented with developmental delay, intellectual disability, motor delay, and behavioural anomalies. Homozygous ablation of the NSUN6 ortholog in Drosophila led to locomotion and learning impairment. The authors concluded that biallelic pathogenic variants in NSUN6 cause one form of autosomal recessive intellectual disability, establishing another link between RNA modification and cognition.
A separate study reported a child with global developmental delay, short stature, and epileptic seizures whose whole exome sequencing identified a de novo pathogenic frameshift variant in ZBTB18 (c.1282_1283del). After treatment with levetiracetam and rehabilitation, seizures were controlled for nearly half a year and psychomotor and language development improved. The authors noted that among 28 children with ZBTB18 mutations, those with frameshift or nonsense mutations had significantly more motor retardation, language retardation, and epilepsy than those with missense mutations. Another abstract described RHOBTB2-related developmental and epileptic encephalopathy 64, caused by de novo missense variants clustering in the BTB domains, with onset of seizures in the first year, severe to profound intellectual disability, movement disorders, and postnatal microcephaly.
A Pakistani family with autosomal recessive intellectual disability (MRT 48) was found to carry a homozygous c.1693T>C variant in SLC6A17, broadening the genotypic spectrum of that gene. A review article noted that balanced chromosomal translocations occur as de novo events in 1 in 2,000 live births and can cause intellectual disability through submicroscopic deletions, duplications, inversions, or disruption of genes at breakpoints, but that cryptic genomic imbalances are very rare and new technologies like long-read genome sequencing could detect breakpoint effects.
No drug is tested or recommended in any of these abstracts. What is still missing for these conditions is systematic patient stratification by specific gene and variant type, larger cohorts to establish genotype-phenotype correlations, and funding for preclinical models that could test whether RNA-modifying enzymes or other targets are druggable.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Genetics in Medicine · 2023 · 20 citations · open access
Biallelic variants in NSUN6 cause an autosomal recessive neurodevelopmental disorder
AbstractPURPOSE: 5-methylcytosine RNA modifications are driven by NSUN methyltransferases. Although variants in NSUN2 and NSUN3 were associated with neurodevelopmental diseases, the physiological role of NSUN6 modifications on transfer RNAs and messenger RNAs remained elusive. METHODS: We combined exome sequencing of consanguineous families with functional characterization to identify a new neurodevelopmental disorder gene. RESULTS: We identified 3 unrelated consanguineous families with deleterious homozygous variants in NSUN6. Two of these variants are predicted to be loss-of-function. One maps to the first exon and is predicted to lead to the absence of NSUN6 via nonsense-mediated decay, whereas we showed that the other maps to the last exon and encodes a protein that does not fold correctly. Likewise, we demonstrated that the missense variant identified in the third family has lost its enzymatic activity and is unable to bind the methyl donor S-adenosyl-L-methionine. The affected individuals present with developmental delay, intellectual disability, motor delay, and behavioral anomalies. Homozygous ablation of the NSUN6 ortholog in Drosophila led to locomotion and learning impairment. CONCLUSION: Our data provide evidence that biallelic pathogenic variants in NSUN6 cause one form of autosomal recessive intellectual disability, establishing another link between RNA modification and cognition.
[Analysis of clinical features and ZBTB18 gene variant in a child with autosomal dominant mental disorder type 22].
AbstractOBJECTIVE: To analyze the clinical characteristics and ZBTB18 gene variant in a child with epilepsy and global developmental delay. METHODS: Clinical data and laboratory examination of the patient were reviewed. Whole exome sequencing (WES) was also carried out for the family trio. RESULTS: The main manifestations of the child included global developmental delay, short stature, epileptic seizures. EEG revealed frequent occurrence of sharp (slow) waves in the right central region during sleeping, with sharp waves occasionally seen in the frontal and right posterior temporal regions. Cranial MRI has shown no obvious abnormality. WES has identified a de novo pathogenic variant in the ZBTB18 gene [NM_205768.3: exon 2: c.1282_1283del (p.Phe428Leufs*72)]. Based on the guidelines from American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PS2+PVS1_Moderate+PM2_Supporting). Following treatment with levetiracetam and rehabilitation, the seizures have been controlled for nearly half a year, with improvement of the psychomotor and language development. So far 28 children have been discovered with ZBTB18 gene mutations, and there was a significant difference in the clinical phenotypes of motor retardation, language retardation and epilepsy between those harboring frameshift/nonsense mutations and missense mutations. CONCLUSION: The c.1282_1283del (p.Phe428leufs *72) variant of the ZBTB18 probably underlay the autosomal dominant mental disorder type 22 in this child. Compared with missense mutations, frameshift/nonsense mutations may predispose more to motor retardation, delayed language development and epilepsy.
Genetics in Medicine Open · 2024 · 1 citations · open access
O42: Development of an anti-sense oligonucleotide therapeutic targeting RhoBTB2-related epileptic encephalopathy
AbstractRHOBTB2 encodes a member of the atypical Rho GTPase containing a GTPase domain and two tandem BTB domains. The BTB domains are involved in interacting with the Cullin3-dependent ubiquitin ligase complex, mediating ubiquitination, and recruiting substrates to the complex. Pathogenic de novo missense variants clustering in the BTB domains were reported to cause autosomal dominant developmental and epileptic encephalopathy 64 [DEE64; OMIM 618004]. DEE64 is a neurodevelopmental disorder characterized by onset of seizures within the first year of life, severe to profound intellectual disability, movement disorders, postnatal microcephaly, and nonspecific dysmorphic features.
Biallelic Variant in <scp> <i>SLC6A17</i> </scp> in a Pakistani Family With Autosomal Recessive Intellectual Disability
AbstractAutosomal recessive intellectual disability affects 1%-3% of the general population and is a major concern in countries where consanguineous marriages are common. Mental retardation autosomal recessive 48 (MRT 48) (OMIM 616269) is a recessive syndromic disorder characterized by progressive tremors, speech impairment, and behavioral problems. In the present study, we highlight a family with a case of MRT 48. The index patient was second born to healthy consanguineous parents with a history of intellectual disability. Whole exome sequencing of the patient was performed, which revealed a homozygous c.1693T>C;p.(Tyr565His) variant in the SLC6A17 gene. The variant segregated in the extended family with the phenotype. This study broadens the genotypic spectrum of SLC6A17 variants.
DOAJ (DOAJ: Directory of Open Access Journals) · 2023 · 0 citations · open access
How might a balanced chromosomal translocation lead to a spectrum of intellectual disabilities in newborns?
AbstractBackground: Intellectual disability (ID) consists of a broad range of disorders characterized by low general intellectual functioning (IQ below 70). ID etiologic causes are heterogeneous, ranging from environmental to chromosomal and monogenic conditions. Although many autosomal genes responsible for ID are expected, but only a small number of these have been identified and up to now most progress has been made in the area of X-linked translocation ID; but many autosomal chromosome genes play a crucial role in the development of a central nervous system. Any change which lead to lose or reduce the function or change the expression of them; high or low, even have a damaging effect on the functional protein might lead to different phenotype like developmental delay, growth retardation or intellectual disabilities. Result & conclusion: In this paper, we discuss the importance of balanced chromosomal translocations in the etiologic cause of newborn intellectual disabilities. Balanced translocation is the result of breaking off two chromosomes and reattached in a way that the sections of two chromosomes have switched places. These rearrangements are found as de novo events in 1/2,000 live births and give rise to some congenital anomalies which is the product of submicroscopic deletions, duplications, inversion or disruption, activation, or inactivation of a gene or different genes located at or near the breakpoints in the basepair level. These apparently balanced translocations due to positional effect lead to occur abnormal phenotype. In conclusion, Cryptic genomic imbalances cause mentality are very rare condition but new technologies like NGS long-read genome sequencing could detect rapid breakpoint effects on live birth healthy and discover a new way for prenatal diagnosis.
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.
