DeCure for Tatton-Brown-Rahman overgrowth syndrome
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Tatton-Brown-Rahman overgrowth syndrome — 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 moduleTatton-Brown-Rahman overgrowth syndrome 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 tatton-brown-rahman overgrowth syndrome 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
DNA methyltransferase 3 alpha (DNMT3A) — DNMT3A 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 sahdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6PA7 · 2.94 Å · ligand S-ADENOSYL-L-HOMOCYSTEINE (SAH). Experimental structure, not a prediction.
What the evidence adds up to
Tatton-Brown-Rahman syndrome is an overgrowth intellectual disability syndrome first described in 2014. A clinical study of 55 individuals with de novo constitutive DNMT3A variants reported intellectual disability and overgrowth in more than 80% of cases, designating these as major clinical associations. Additional frequent features, reported in 20–80% of individuals, included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity defined as weight ≥2 standard deviations (67%); hypotonia (54%); behavioural or psychiatric issues, most frequently autistic spectrum disorder (51%); kyphoscoliosis (33%); and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years.
A separate report described the first Korean family with maternally inherited TBRS due to a novel heterozygous DNMT3A variant c.118G>C p.(Glu40Gln), located outside the main functional domain. The patient and her mother had typical clinical features including tall stature during childhood, macrocephaly, intellectual disability, and characteristic facial appearance. The authors noted that TBRS shows milder dysmorphic features than other overgrowth syndromes, potentially leading to underdiagnosis and underestimated prevalence.
A case report of an 8-month-old girl with psychomotor retardation, hypotonia, ventricular enlargement, and tonsillar hernia malformation identified a novel heterozygous mutation c.134C>T(p.A45V) in the DNMT3A gene, confirmed as de novo. The authors stated that TBRS often has a good prognosis, with overgrowth and mental retardation as the most common manifestations, and that behavioural and psychiatric problems, scoliosis, and afebrile seizures are possible complications.
No drug treatment or intervention is mentioned in any of these abstracts. What remains missing is any clinical trial testing a therapy, any preclinical work on a molecular target for this syndrome, and any systematic effort to stratify patients by specific DNMT3A variant type or functional domain to guide future treatment development.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Wellcome Open Research · 2018 · 114 citations · open access
The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants
Abstract<ns3:p> Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous <ns3:italic>DNMT3A</ns3:italic> variants. Here we have undertaken a detailed clinical study of 55 individuals with <ns3:italic>de novo</ns3:italic> <ns3:italic>DNMT3A</ns3:italic> variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS </ns3:p>
Annals of Pediatric Endocrinology & Metabolism · 2019 · 5 citations · open access
First identified Korean family with Tatton-Brown-Rahman Syndrome caused by the novel DNMT3A variant c.118G&gt;C p.(Glu40Gln)
AbstractTatton-Brown-Rahman Syndrome (TBRS), an overgrowth syndrome caused by heterozygous mutation of DNMT3A, first was described in 2014. Approximately 60 DNMT3A variants, including 32 missense variants, have been reported, with most missense mutations located on the DNMT3A functional domains. Autosomal dominant inheritance by germ-line mutation of DNMT3A has been reported, but vertical transmission within a family is extremely rare. Herein, we report the first Korean family with maternally inherited TBRS due to the novel heterozygous DNMT3A variant c.118G>C p.(Glu40Gln), located outside the main functional domain and identified by multigene panel sequencing. The patient and her mother had typical clinical features, including tall stature during childhood, macrocephaly, intellectual disability, and characteristic facial appearance. TBRS shows milder dysmorphic features than other overgrowth syndromes, potentially leading to underdiagnosis and underestimated prevalence; thus, targeted multigene panel sequencing including DNMT3A will be a useful tool in cases of overgrowth and unexplained mild intellectual disability for early diagnosis and genetic counseling.
American Journal of Medical Genetics Part A · 2023 · 2 citations · open access
<scp>Tatton‐Brown–Rahman</scp> syndrome: Novel pathogenic variants and new neuroimaging findings
AbstractTatton-Brown-Rahman syndrome (TBRS) or DNMT3A-overgrowth syndrome is characterized by overgrowth and intellectual disability associated with minor dysmorphic features, obesity, and behavioral problems. It is caused by variants of the DNMT3A gene. We report four patients with this syndrome due to de novo DNMT3A pathogenic variants, contributing to a deeper understanding of the genetic basis and pathophysiology of this autosomal dominant syndrome. Clinical and magnetic resonance imaging assessments were also performed. All patients showed corpus callosum anomalies, small posterior fossa, and a deep left Sylvian fissure; as well as asymmetry of the uncinate and arcuate fascicles and marked increased cortical thickness. These results suggest that structural neuroimaging anomalies have been previously overlooked, where corpus callosum and brain tract alterations might be unrecognized neuroimaging traits of TBRS syndrome caused by DNMT3A variants.
[Tatton-Brown-Rahman syndrome associated with the DNMT3A gene: a case report and literature review].
AbstractThis article reports the clinical and genetic features of a case of Tatton-Brown-Rahman syndrome (TBRS) caused by DNMT3A gene mutation. A girl, aged 8 months and 14 days, had the clinical manifestations of psychomotor retardation, hypotonia, ventricular enlargement, and tonsillar hernia malformation. Gene analysis identified a novel heterozygous mutation, c.134C>T(p.A45V), in the DNMT3A gene, and the wild type was observed at this locus in her parents. This mutation was determined as a possible pathogenic mutation according to the guidelines of American College of Medical Genetics and Genomics, which had not been reported in previous studies and conformed to autosomal dominant inheritance. This child was diagnosed with TBRS. TBRS often has a good prognosis, with overgrowth and mental retardation as the most common clinical manifestations, and behavioral and psychiatric problems, scoliosis, and afebrile seizures are possible complications of TBRS. The possibility of TBRS should be considered for children with overgrowth and mental retardation, and genetic diagnosis should be conducted when necessary.
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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