DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Kleefstra syndrome 1 — screening already-approved drugs against its 4-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleKleefstra syndrome 1 maps to a 4-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 kleefstra syndrome 1 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
euchromatic histone lysine methyltransferase 1 (EHMT1) — EHMT1 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…
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RCSB Protein Data Bank · entry 6BY9 · 2.3 Å · ligand UNKNOWN ATOM OR ION (UNX). Experimental structure, not a prediction.
What the evidence adds up to
Kleefstra syndrome is a rare genetic disorder caused by disruption of the euchromatin histone methyl transferase 1 gene (EHMT1) on chromosome 9q34.3 or, in Kleefstra syndrome 2, by loss-of-function variants in the KMT2C gene. The estimated frequency is 1 in 200,000 cases of mental retardation, and approximately 110 patients have been reported in the literature. Core features include moderate to severe intellectual disability, developmental delay, childhood hypotonia, brachycephaly or microcephaly, characteristic facial dysmorphism (flat face, hypertelorism, short nose with anteverted nostrils, thickened lower lip, carp-mouth with macroglossia, unusual eyebrow shape), and autism spectrum disorder. Epilepsy is common. Macrocephaly and enuresis have also been noted in some patients.
Two Hungarian patients were described in 2016, one with the classic phenotype and a second who additionally showed an abnormal antiepileptic drug metabolic response. Array CGH in the second patient revealed a 1.211 Mb deletion in the 9q subtelomeric region. In 2021, recurrence in siblings due to a paternal mosaic mutation was reported: a male and female sibling with asymptomatic parents both carried an EHMT1 mutation and presented with the typical core phenotype, plus macrocephaly and enuresis (the latter not previously described). Reverse phenotyping in the father identified inguinal hernia, azoospermia, and possible behavioural disorders. A 2022 case described an eight-month-old boy with Kleefstra syndrome type 2 due to a novel de novo pathogenic mutation in KMT2C, who also had severe sensorineural deafness.
A 2025 case report provided a ten-year follow-up of an adult with Kleefstra syndrome 2 caused by a novel heterozygous nonsense variant in KMT2C (c.3940C>T, p.Gln1314Ter). This patient developed proteinuria with progressive kidney dysfunction due to focal segmental glomerular sclerosis, and later experienced recurrent episodes mimicking mitochondrial stroke-like episodes, including encephalopathy, focal status epilepticus with impaired consciousness, and cortical/subcortical T2/FLAIR signal hyperintensities. These episodes partially responded to intravenous arginine infusions. Nuclear and mitochondrial DNA variants associated with mitochondrial disorders were excluded. The authors note that these multi-organ manifestations—nephrotic disease and stroke-like episodes—have not been previously reported in Kleefstra syndrome 2.
What remains missing is systematic long-term follow-up data on multi-organ involvement across larger cohorts, particularly for Kleefstra syndrome 2. No clinical trials or interventional studies are reported. The evidence is limited to case reports and small case series, with no data on prevalence of the described renal or neurological complications. Patient stratification by genetic subtype (EHMT1 deletion versus KMT2C variant) and prospective natural history studies would be needed to clarify the full phenotypic spectrum and guide monitoring.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Molecular Cytogenetics · 2016 · 20 citations · open access
Kleefstra syndrome in Hungarian patients: additional symptoms besides the classic phenotype
AbstractBACKGROUND: Kleefstra syndrome is a rare genetic disorder, with core phenotypic features encompassing developmental delay/intellectual disability, characteristic facial features - brachy(micro)cephaly, unusual shaped eyebrows, flat face with hypertelorism, short nose with anteverted nostrils, thickened lower lip, carpmouth with macroglossia - and childhood hypotonia. Some additional symptoms are observed in different percentage of the patients. Epilepsy is common symptom as well. The underlying cause of the syndrome is a submicroscopic deletion in the chromosomal region 9q34.3 or disruption of the euchromatin histone methyl transferase 1. CASE PRESENTATION: We describe two Hungarian Kleefstra syndrome patients, one with the classic phenotype of the syndrome, the diagnosis was confirmed by subtelomeric FISH. Meanwhile in our second patient beside the classic phenotype a new symptom - abnormal antiepileptic drug metabolic response - could be observed. Subtelomere FISH confirmed the 9q34.3 terminal deletion. Because of the abnormal drug metabolism in our second patient, we performed array CGH analysis as well searching for other rearrangements. Array CGH analysis indicated a large - 1.211 Mb -, deletion only in the 9q subtelomeric region with breakpoints ch9:139,641,471-140,852,911. CONCLUSIONS: This is the first report on Kleefstra syndrome in patients describing a classical and a complex phenotype involving altered drug metabolism.
Journal of College of Physicians And Surgeons Pakistan · 2022 · 7 citations · open access
Kleefstra Syndrome
AbstractKleefstra syndrome (KS), previously referred to as 9q subtelomeric deletion syndrome (9qSTDS), is characterised by moderate to severe developmental delay/mental retardation, childhood hypotonia, and brachy-microcephaly (main clinical phenotype), midface hypoplasia, prognathism, lip and eyebrow shape anomalies. The true prevalence of KS is unknown, but it is estimated that it occurs with a frequency of 1/200.000 in cases with mental retardation. On literature search, approximately 110 patients have been reported so far. Genetic analysis should be planned and interdisciplinary monitoring should be provided in cases suspected to have KS. Key Words: Child, Genetic disorder, Kleefstra Syndrome, Dysmorphism.
Journal of College of Physicians And Surgeons Pakistan · 2022 · 5 citations · open access
Kleefstra Syndrome with Severe Sensory Neural Deafness and <em>De Novo</em> Novel Mutation
AbstractKleefstra syndrome is a rare inherited neuro-developmental condition characterised by facial dysmorphism, microcephaly, hypotonia, developmental delay, and intellectual disability. It is a rare syndrome; and less than 100 cases with different genetic mutations are reported so far. We report an eight-month baby boy with Kleefstra syndrome type 2 due to a novel de novo pathogenic mutation in the KMT2C (Lysine methyltransferase 2C) gene. Key Words: Kleefstra syndrome, KMT2C gene, Neurodevelopmental disorder, Deafness.
American Journal of Medical Genetics Part A · 2021 · 2 citations
Kleefstra syndrome: Recurrence in siblings due to a paternal mosaic mutation
AbstractKleefstra syndrome (KS) is a rare autosomic dominant genetic disorder caused by euchromatic histone methyltransferase 1 (EHMT1) alterations. Patients mainly present with moderate to severe intellectual disability, a severe delay in/or absence of speech, autism spectrum disorder, childhood hypotonia, neuropsychiatric anomalies, and distinctive dysmorphic features. Here, we report the cases of a male and a female, two younger siblings of three, with asymptomatic parents. An EHMT1 new mutation was identified. Both presented with a typical core phenotype. Some specific features were noted, such as macrocephaly (previously reported) and enuresis (not yet described). Parental analysis identified the mutation in the mosaic state in the father. Reverse phenotyping enabled us to highlight the pauci phenotype features of inguinal hernia, azoospermia, and possible behavioral disorders. This allowed us to adapt his follow-up and genetic counseling for the family. Our three reported cases provide a new description of KS with an intragenic EHMT1 mutation, whereas in the literature most reported cases have EHMT1 deletions. Moreover, in the areas of next-generation sequencing and trio techniques with parental segregation, it is important to remain cautious about disregarding variants based on an autosomal recessive hypothesis.
Long term follow-up of multiorgan disease in Kleefstra syndrome 2 in an adult – case report
AbstractAbstract Objectives The Kleefstra syndrome spectrum (KSS) is a group of neurodevelopmental disorders characterized by intellectual disability, behavioral disorders, growth and neurodevelopmental delay, facial dysmorphism and neurological deficits. Kleefstra syndrome 2 (KLEFS2) is a part of KSS and is due to heterozygous loss-of-function variants in the KMT2 C gene. We report the long-term clinical course and multi-organ manifestations of a patient with KLEFS2 caused by a novel heterozygous pathogenic variant in KMT2 C. Methods A patient with KSS phenotype developed proteinuria with progressive kidney dysfunction secondary to focal segmental glomerular sclerosis. She subsequently developed recurrent episodes that mimicked mitochondrial stroke-like episodes. The phenotype included encephalopathy, stroke-like episodes with focal status epilepticus with impaired consciousness associated with cortical and subcortical T2/FLAIR signal hyperintensities that partially responded to intravenous arginine infusions. Results Exome sequencing revealed a heterozygous pathogenic nonsense variant in KMT2 C (NM_170606.3) c.3940C > T (p.Gln1314Ter). Nuclear and mitochondrial DNA variants associated with mitochondrial disorders have been excluded. Discussion This is a case of KLEFS2 with longitudinal 10 year follow up and its previously unreported multi-organ clinical manifestations including stroke-like episodes and nephrotic disease. Our report further expands the phenotypic spectrum of KLEFS2. Further reports of patients with KLEFS2 with multi-organ involvement should be sought to confirm our findings.
Long term follow-up of multiorgan disease in Kleefstra syndrome 2 in an adult – case report
AbstractAbstract Objectives The Kleefstra syndrome spectrum (KSS) is a group of neurodevelopmental disorders characterized by intellectual disability, behavioral disorders, growth and neurodevelopmental delay, facial dysmorphism and neurological deficits. Kleefstra syndrome 2 (KLEFS2) is a part of KSS and is due to heterozygous loss-of-function variants in the KMT2 C gene. We report the long-term clinical course and multi-organ manifestations of a patient with KLEFS2 caused by a novel heterozygous pathogenic variant in KMT2 C. Methods A patient with KSS phenotype developed proteinuria with progressive kidney dysfunction secondary to focal segmental glomerular sclerosis. She subsequently developed recurrent episodes that mimicked mitochondrial stroke-like episodes. The phenotype included encephalopathy, stroke-like episodes with focal status epilepticus with impaired consciousness associated with cortical and subcortical T2/FLAIR signal hyperintensities that partially responded to intravenous arginine infusions. Results Exome sequencing revealed a heterozygous pathogenic nonsense variant in KMT2 C (NM_170606.3) c.3940C > T (p.Gln1314Ter). Nuclear and mitochondrial DNA variants associated with mitochondrial disorders have been excluded. Discussion This is a case of KLEFS2 with longitudinal 10 year follow up and its previously unreported multi-organ clinical manifestations including stroke-like episodes and nephrotic disease. Our report further expands the phenotypic spectrum of KLEFS2. Further reports of patients with KLEFS2 with multi-organ involvement should be sought to confirm our findings.
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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