DeCure for Macrocephaly-developmental delay syndrome
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for macrocephaly-developmental delay syndrome — screening already-approved drugs against its 5-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMacrocephaly-developmental delay syndrome maps to a 5-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 macrocephaly-developmental delay 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
RAB5C, member RAS oncogene family (RAB5C) — RAB5C 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 gnpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4KYI · 3.075 Å · ligand PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER (GNP). Experimental structure, not a prediction.
What the evidence adds up to
Pathogenic, heterozygous, mostly de novo variants in WDFY3 were identified in 13 individuals as a monogenic cause of mild to moderate neurodevelopmental delay, with significant de novo enrichment (P = 0.003). Nine variants were protein-truncating and four were missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders such as autism spectrum disorder and attention deficit hyperactivity disorder. One proband with a missense variant in the PH-domain of WDFY3 presented with microcephaly, an opposing phenotype. In mice, Wdfy3-haploinsufficient animals displayed macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. The authors propose that WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway, while PH-domain variants lead to microcephaly via canonical Wnt-pathway upregulation.
In five unrelated individuals with global developmental delay, intellectual disability, dysmorphic facial features, and frequent microcephaly, de novo predicted loss-of-function variants were identified in CHAMP1, a zinc finger protein involved in kinetochore-microtubule attachment required for proper chromosome alignment during mitosis. These findings are consistent with de novo CHAMP1 mutations reported in five other individuals with similar features. The authors suggest that mutations in CHAMP1 may affect cell division and hence brain development and function, resulting in developmental delay and intellectual disability.
A population-based cross-sectional study in one Mexican state administered the Child Development Evaluation (CDE) test to 11,455 children aged 16 to 59 months. Of the 6.2% (n = 714) identified as at risk of delay, 355 were included in a diagnostic evaluation using the Battelle Development Inventory, 2nd edition. Developmental delay was corroborated in at least one domain in 93.2% of participants. The proportion of delay per domain was: communication 82.5%, cognitive 80.8%, motor 55.5%, adaptive 41.7%, and social-personal 33.8%. False positives (Total Development Quotient > 90) accounted for 6.5% of the sample, and 6.8% had no domain with delay.
A literature review of the term "neuropsychomotor developmental delay" (NPMD) from 1940 to 2013 selected 71 articles. The terms "developmental delay" and "global developmental delay" were most frequent in international literature; in Brazil, "delayed NPMD" was most used. The term emerged internationally in the mid-1940s and gained momentum in the 1990s. Among the reviewed articles, 34 presented definitions, and 16 different concepts were identified. The review found heterogeneous concepts and various applications of the term, with no standardised definition found in Brazilian publications. What remains missing is a standardised definition of developmental delay for clinical and research use, and any trial or treatment data for the genetic forms described — the WDFY3 and CHAMP1 findings are purely genetic association studies with no therapeutic intervention tested.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Brain · 2019 · 53 citations · open access
Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size
AbstractThe underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.
Molecular Case Studies · 2015 · 44 citations · open access
De novo pathogenic variants in <i>CHAMP1</i> are associated with global developmental delay, intellectual disability, and dysmorphic facial features
AbstractWe identified five unrelated individuals with significant global developmental delay and intellectual disability (ID), dysmorphic facial features and frequent microcephaly, and de novo predicted loss-of-function variants in chromosome alignment maintaining phosphoprotein 1 (CHAMP1). Our findings are consistent with recently reported de novo mutations in CHAMP1 in five other individuals with similar features. CHAMP1 is a zinc finger protein involved in kinetochore-microtubule attachment and is required for regulating the proper alignment of chromosomes during metaphase in mitosis. Mutations in CHAMP1 may affect cell division and hence brain development and function, resulting in developmental delay and ID.
Boletín Médico del Hospital Infantil de México · 2015 · 22 citations · open access
Evaluación diagnóstica del nivel de desarrollo en niños identificados con riesgo de retraso mediante la prueba de Evaluación del Desarrollo Infantil
AbstractLa prueba Evaluación del Desarrollo Infantil (EDI), diseñada en México, clasifica a los niños de acuerdo con su desarrollo en desarrollo normal, rezago en el desarrollo y riesgo de retraso. La versión modificada se desarrolló y validó, pero no se conocen sus propiedades en base poblacional. El objetivo de este trabajo fue establecer la confirmación diagnóstica en niños de 16 a 59 meses identificados con riesgo de retraso por la prueba EDI. Se realizó un estudio transversal de base poblacional en una entidad federativa de México. Se aplicó la prueba EDI a 11,455 niños de 16 a 59 meses, de diciembre de 2013 a marzo de 2014. Se consideró como población elegible al 6.2% (n = 714) que obtuvo como resultado riesgo de retraso. Para la inclusión en el estudio se realizó una aleatorización estratificada por bloques para sexo y grupo de edad. A cada participante se le realizó la evaluación diagnóstica utilizando el Inventario de Desarrollo de Battelle 2ª. edición. De los 355 participantes incluidos, el 65.9% fue de sexo masculino y el 80.2% de medio rural. El 6.5% fueron falsos positivos (cociente total de desarrollo ˃ 90) y el 6.8% no tuvo ningún dominio con retraso (cociente de desarrollo de dominio < 80). Se calculó la proporción de retraso en las siguientes áreas: comunicación (82.5%), cognitivo (80.8%), personal-social (33.8%), motor (55.5%) y adaptativo (41.7%). Se observaron diferencias en los porcentajes de retraso por edad y dominio/subdominio evaluado. Se corroboró la presencia de retraso en al menos un dominio evaluado por la prueba diagnóstica en el 93.2% de la población estudiada. The Child Development Evaluation (or CDE Test) was developed in Mexico as a screening tool for child developmental problems. It yields three possible results: normal, slow development or risk of delay. The modified version was elaborated using the information obtained during the validation study but its properties according to the base population are not known. The objective of this work was to establish diagnostic confirmation of developmental delay in children 16- to 59-months of age previously identified as having risk of delay through the CDE Test in primary care facilities. A population-based cross-sectional study was conducted in one Mexican state. CDE test was administered to 11,455 children 16- to 59-months of age from December/2013 to March/2014. The eligible population represented the 6.2% of the children (n = 714) who were identified at risk of delay through the CDE Test. For inclusion in the study, a block randomization stratified by sex and age group was performed. Each participant included in the study had a diagnostic evaluation using the Battelle Development Inventory, 2nd edition. From the 355 participants included with risk of delay, 65.9% were male and 80.2% were from rural areas; 6.5% were false positives (Total Development Quotient ˃90) and 6.8% did not have any domain with delay (Domain Developmental Quotient <80). The proportion of delay for each domain was as follows: communication 82.5%; cognitive 80.8%; social-personal 33.8%; motor 55.5%; and adaptive 41.7%. There were significant differences in the percentages of delay both by age and by domain/subdomain evaluated. In 93.2% of the participants, developmental delay was corroborated in at least one domain evaluated.
Revista Paulista de Pediatria (English Edition) · 2015 · 11 citations · open access
Neuropsychomotor developmental delay: conceptual map, term definitions, uses and limitations
AbstractTo retrieve the origin of the term neuropsychomotor developmental delay” (NPMD), its conceptual evolution over time, and to build a conceptual map based on literature review. A literature search was performed in the SciELO Brazil, Web of Science, Science Direct, OneFile (GALE), Pubmed (Medline), Whiley Online, and Springer databases, from January of 1940 to January of 2013, using the following keywords: NPMD delay, NPMD retardation, developmental delay, and global developmental delay. A total of 71 articles were selected, which were used to build the conceptual map of the term. Of the 71 references, 55 were international and 16 national. The terms developmental delay and global developmental delay were the most frequently used in the international literature and, in Brazil, delayed NPMD was the most often used. The term developmental delay emerged in the mid 1940s, gaining momentum in the 1990s. In Brazil, the term delayed NPMD started to be used in the 1980s, and has been frequently cited and published in the literature. Delayed development was a characteristic of 13 morbidities described in 23 references. Regarding the type of use, 19 references were found, with seven forms of use. Among the references, 34 had definitions of the term, and 16 different concepts were identified. Developmental delay is addressed in the international and national literature under different names, various applications, and heterogeneous concepts. Internationally, ways to improve communication between professionals have been indicated, with standardized definition of the term and use in very specific situations up to the fifth year of life, which was not found in Brazilian publications. Resgatar a origem do termo atraso do desenvolvimento neuropsicomotor (DNPM), sua evolução conceitual ao longo do tempo e construir mapa conceitual do termo com base em busca bibliográfica. Foi realizada busca nas bases de dados eletrônicas do Portal da Capes, que incluem Scielo Brazil, Web of Science, Science Direct, OneFile (GALE), Pubmed (Medline), Whiley Online e Springer, referente a Janeiro/1940-Janeiro/2013. Palavras-chave: atraso e retardo do DNPM, developmental delay e global developmental delay. Foram selecionados 71 artigos e construído o mapa conceitual do termo. Das 71 referências, 55 eram internacionais e 16 nacionais. Os termos mais encontrados foram global developmental delay e developmental delay na literatura internacional e retardo e atraso do DNPM no Brasil. Internacionalmente, o termo surgiu em meados da década de 40 ganhando força nos anos 90. No Brasil, o termo começou a ser usado na década de 80 e vem sendo frequentemente citado na literatura. O atraso é citado em 23 trabalhos como característica presente em 13 tipos de condições clínicas. Com relação ao uso, foram encontrados 19 estudos, com sete situações de uso. Dentre os artigos revisados, 34 deles apresentaram definições, sendo identificados 16 conceitos diferentes. O atraso do desenvolvimento é abordado na literatura internacional e nacional sob diversos nomes, diferentes aplicações e conceitos heterogêneos. Internacionalmente, apontam-se caminhos para melhorar a comunicação entre profissionais, com definição padronizada do termo e uso em situações específicas até o quinto ano de vida, o que não foi encontrado nas publicações nacionais.
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.
