DeCure for Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome
DeCure's autonomous Cardio AI scientist is researching a drug-repurposing hypothesis for autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome — 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 intellectual disability-craniofacial anomalies-cardiac defects syndrome 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 intellectual disability-craniofacial anomalies-cardiac defects 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
lysine acetyltransferase 6A (KAT6A) — KAT6A 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 cmcdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9DZN · 1.724 Å · ligand CARBOXYMETHYL COENZYME *A (CMC). Experimental structure, not a prediction.
What the evidence adds up to
A 2017 study of MED13L haploinsufficiency, based on two new patients and a review of prior reports, found moderate to severe intellectual disability and facial anomalies in all patients, with severe speech delay and muscular hypotonia in most. Common signs included abnormal MRI findings of myelination defects and abnormal corpus callosum, ataxia, coordination problems, autistic features, seizures or abnormal EEG, and congenital heart defects, each present in about 20–50% of patients. The authors noted that many published missense mutations remain variants of uncertain significance, though one recurrent missense mutation (p.(Asp860Gly)) was predicted to destabilise an alpha-helix. They concluded that further detailed patient descriptions are needed to explore the full clinical spectrum and the role of missense mutations.
A 1985 report described six relatives across three generations with an autosomal dominant syndrome of mild prenatal-onset growth deficiency, characteristic facial appearance, preauricular pits, fifth finger clinodactyly, and tetralogy of Fallot in three of them. The clinical impact appeared related to the severity of the cardiac defect. A 2014 report documented a fourth familial case of cardiofaciocutaneous syndrome, caused by a novel MEK2 mutation, transmitted from father to son, noting that vertical transmission appears associated with rare mutations and relatively mild intellectual disability.
A 2020 report described a patient with a de novo BMP2 nonsense variant who exhibited craniofacial and skeletal features previously linked to BMP2 haploinsufficiency and the novel findings of bicuspid aortic valve and aortic root aneurysm. The authors stated this provided another potential cause of bicuspid aortic valve and confirmed BMP2’s role in left ventricular outflow development. A 2015 case report of a 38-year-old man with Ellis-van Creveld syndrome, an autosomal recessive disorder with cardiac defects in about 50% of cases, described two surgical corrections for cardiac anomalies and aimed to supplement information on the clinical course in older patients.
What remains missing is a unified clinical trial or systematic natural history study that includes all these genetic causes under one protocol. No drug intervention is tested in any of these abstracts. Patient stratification by specific gene mutation and by cardiac defect severity is not yet standardised. Funding for long-term follow-up of adults with these rare syndromes is lacking.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
European Journal of Medical Genetics · 2017 · 51 citations · open access
Genotype-phenotype evaluation of MED13L defects in the light of a novel truncating and a recurrent missense mutation
AbstractA decade after the designation of MED13L as a gene and its link to intellectual disability (ID) and dextro-looped transposition of great arteries in 2003, we previously described a recognizable syndrome due to MED13L haploinsufficiency. Subsequent reports of 22 further patients diagnosed by genome-wide testing further delineated the syndrome with expansion of the phenotypic spectrum and showed reduced penetrance for congenital heart defects. We now report two novel patients identified by whole exome sequencing, one with a de novo MED13L truncating mutation and the other with a de novo missense mutation. The first patient indicates some facial resemblance to Kleefstra syndrome as a novel differential diagnosis, and the second patient shows, for the first time, recurrence of a MED13L missense mutation (p.(Asp860Gly)). Notably, our in silico modelling predicted this missense mutation to decrease the stability of an alpha-helix and thereby affecting the MED13L secondary structure, while the majority of published missense mutations remain variants of uncertain significance. Review of the reported patients with MED13L haploinsufficiency indicates moderate to severe ID and facial anomalies in all patients, as well as severe speech delay and muscular hypotonia in the majority. Further common signs include abnormal MRI findings of myelination defects and abnormal corpus callosum, ataxia and coordination problems, autistic features, seizures/abnormal EEG, or congenital heart defects, present in about 20-50% of the patients. With reference to facial anomalies, the majority of patients were reported to show broad/prominent forehead, low set ears, bitemporal narrowing, upslanting palpebral fissures, depressed/flat nasal bridge, bulbous nose, and abnormal chin, but macroglossia and horizontal eyebrows were also observed in ∼30%. The latter are especially important in the differential diagnosis of 1p36 deletion and Kleefstra syndromes, while the more common facial gestalt shows some resemblance to 22q11.2 deletion syndrome. Despite the fact that MED13L was found to be one of the most common ID genes in the Deciphering Developmental Disorders Study, further detailed patient descriptions are needed to explore the full clinical spectrum, potential genotype-phenotype correlations, as well as the role of missense mutations and potential mutational hotspots along the gene.
American Journal of Medical Genetics · 1985 · 17 citations
An autosomal dominant syndrome of characteristic facial appearance, preauricular pits, fifth finger clinodactyly, and tetralogy of fallot
AbstractThis report describes six relatives with a syndrome of mild prenatal-onset growth deficiency, an altered craniofacial appearance, preauricular pits, and clinodactyly of the fifth finger; three had tetralogy of Fallot. The clinical impact of this condition appears to be related to the severity of the cardiac defect. Autosomal dominant inheritance is implied by the occurrence of the disorder in three successive generations with documented male-to-male transmission. Recognition of this syndrome is important in counseling families regarding recurrence risk for tetralogy of Fallot.
American Journal of Medical Genetics Part A · 2014 · 9 citations
Familial cardiofaciocutaneous syndrome in a father and a son with a novel MEK2 mutation
AbstractCardiofaciocutaneous (CFC) syndrome is a rare genetic disorder belonging to the group of RASopathies. It is typically characterized by congenital heart defects, short stature, dysmorphic craniofacial features, intellectual disability, failure to thrive, and ectodermal abnormalities such as hyperkeratosis and sparse, brittle, curly hair. CFC syndrome is caused by dominant mutations in one of the four genes BRAF, MEK1, MEK2, and KRAS. Only three familial cases of CFC syndrome have been reported to date, whereas the vast majorities are sporadic cases due to de novo mutations. We report on a fourth familial case with transmission of CFC syndrome from father to son due to a novel heterozygous sequence change c.376A>G (p.N126D) in exon 3 of MEK2 gene. This observation further documents the possibility of vertical transmission of CFC syndrome, which appears to be associated with rare mutations and relatively mild intellectual disability in affected individual. The hypomorphic effect of specific mutations particularly regarding neurocognitive issues may be related to the variable fertility of affected individuals.
American Journal of Medical Genetics Part A · 2020 · 7 citations · open access
A <i>de novo</i> pathogenic <scp><i>BMP2</i></scp> variant‐related phenotype with the novel finding of bicuspid aortic valve
AbstractA rare autosomal dominant syndrome with craniofacial dysmorphisms, skeletal abnormalities, short stature, and congenital heart defects has recently been described, associated with monoallelic truncating and frameshift bone morphogenetic protein 2 (BMP2) variants and deletions. We describe a patient harboring a novel de novo BMP2 nonsense variant, who exhibited craniofacial and skeletal features previously described for this trait and the novel findings of bicuspid aortic valve (BAV) and aortic root and ascending aortic aneurysm. This first instance of aortic valve involvement provides another potential cause of BAV and confirms the role of BMP2 in left ventricular outflow development.
Singapore Medical Journal · 2015 · 3 citations · open access
Ellis-van Creveld syndrome in adulthood: extending the clinical spectrum
AbstractEllis-van Creveld (EvC) syndrome is a rare autosomal recessive malformation disorder. Cardiac defects are observed in about 50% of EvC cases. Surgical data is lacking on the prognosis and life expectancy of EvC patients. Herein, we report the case of a 38-year-old man with EvC syndrome who underwent two surgical corrections for cardiac anomalies. This report supplements the available information on the clinical course of EvC syndrome in older patients.
American Journal of Medical Genetics Part A · 2014 · 0 citations · open access
In this issue
Abstractexplore facial features associated with Mowat-Wilson syndrome (MWS).MWS is characterized by moderate to severe intellectual disability and distinctive facial features associated with congenital heart disease, Hirschsprung disease, hypospadias, agenesis of the corpus callosum, short stature, epilepsy, and microcephaly.Less-common clinical features include ocular anomalies, craniosynostosis, mild intellectual disability, and choanal atresia.Children with these less-common features may be more difficult to diagnose.In this issue Wenger et al report on 28 patients with MWS who have molecularly confirmed ZEB2 mutations, including seven patients with an uncommon presenting feature.Among those with unusual features, two patients had clinical features of CHARGE syndrome, including choanal atresia, coloboma, cardiac defects, genitourinary anomaly, and severe intellectual disability; two patients had craniosynostosis; and three patients had mild intellectual disability.Sixteen patients had previously unreported mutations in ZEB2.The researchers suggest genotypephenotype correlations in patients with mild intellectual disability, two who had a novel missense mutation in ZEB2 and one with a novel splice site mutation in the gene.The researchers contend that identifying these patients highlights the importance of facial gestalt in the accurate identification of MWS when less-common features are present.
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.
