DeCure for Neutropenia, severe congenital, 8, autosomal dominant
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for neutropenia, severe congenital, 8, autosomal dominant — 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 moduleNeutropenia, severe congenital, 8, autosomal dominant 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 neutropenia, severe congenital, 8, autosomal dominant 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
Severe congenital neutropenia has an estimated incidence of 1 in 200,000 individuals of European descent, with many cases inherited in an autosomal dominant pattern. Mutations in the neutrophil elastase gene ELA2 (also called ELANE) were identified in 1999 and have been found in cyclic, sporadic and autosomal dominant neutropenia. In one reported case, a 5-year-old girl with recurrent skin and respiratory infections was found to carry a heterozygous mutation in exon 2 of ELANE (c.157C>G, p.His53Asp), a variant not previously described at the exon coding level but considered clinically relevant because of its location within a hotspot and the autosomal dominant inheritance pattern.
Homozygous mutations in the antiapoptotic gene HAX1 were found in patients with autosomal recessive severe congenital neutropenia. A five-generation family segregating a novel single nucleotide variant in TCIRG1 showed perfect cosegregation with congenital neutropenia: all 11 affected individuals carried the variant, none of the unaffected did. Western blot analysis showed reduced levels of TCIRG1 protein in affected individuals compared to healthy controls. Two unrelated patients with severe congenital neutropenia were heterozygous for different rare, highly conserved coding variants in TCIRG1.
Despite these identified genes, the genetic basis for more than 30% of cases remains unknown. Ongoing linkage studies suggest that additional, as yet unidentified, genes may be involved. In some patients, congenital neutropenia is not isolated but associated with lymphoid immunodeficiency and pigmentation defects such as Chédiak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2, or deficiency of the endosomal adaptor p14.
What is still missing is a complete genetic classification system that accounts for all cases, particularly the more than 30% with unknown genetic cause. No clinical trial data on treatment outcomes specific to these newly identified genetic subtypes were provided in these abstracts. Patient stratification by genotype remains incomplete, and the functional consequences of many variants, including the novel ELANE mutation, require further validation in larger cohorts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Current Opinion in Rheumatology · 2007 · 29 citations
Severe congenital neutropenia: new genes explain an old disease
AbstractPURPOSE OF REVIEW: This review summarizes the recent advances in the diagnosis and molecular characterization of isolated and syndromal forms of severe congenital neutropenia. RECENT FINDINGS: It has become evident that severe congenital neutropenia comprises several genetically distinct entities. In 1999, mutations were identified in the neutrophil elastase gene ELA2. ELA2 mutations have been found in cyclic, sporadic and autosomal dominant neutropenia. Recently, homozygous mutations in the antiapoptotic gene HAX1 were found in patients with autosomal recessive severe congenital neutropenia. Ongoing linkage studies suggest that more and, as yet unidentified, genes may be involved in the pathophysiology of severe congenital neutropenia. In other patients, congenital neutropenia is not an isolated finding but is associated with other abnormalities, in particular, lymphoid immunodeficiency and pigmentation defects such as Chédiak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2, or deficiency of the endosomal adaptor p14. The molecular identification of these disorders originating from mutations in lysosome (related) proteins has advanced our knowledge of intracellular protein trafficking. SUMMARY: Recent insights into the molecular etiology of severe congenital neutropenia provide the opportunity for a definitive genetic classification system. Based on this knowledge, disease-related risks may be recognized and optimized therapeutic options may become available.
AbstractIn 1950 Rolf Kostmann discovered autosomal recessive severe congenital neutropenia and for more than 50 years its molecular etiology has remained enigmatic. In the last years, however, there have been impressive advances in this field. In this perspective article, Dr. Klein summarizes our current knowledge of the molecular basis of congenital neutropenia. See related paper on page 1449.
Dialnet (Universidad de la Rioja) · 2009 · 3 citations
PRODUCTIONS OF GREEK AND ROMAN DRAMA ON THE CZECH STAGE 2001-2009
AbstractSevere congenital neutropenia (SCN) is a rare hematopoietic disorder, with estimated incidence of 1 in 200,000 individuals of European descent, many cases of which are inherited in an autosomal dominant pattern. Despite the fact that several causal genes have been identified, the genetic basis for >30% of cases remains unknown. We report a five-generation family segregating a novel single nucleotide variant (SNV) in TCIRG1. There is perfect cosegregation of the SNV with congenital neutropenia in this family; all 11 affected, but none of the unaffected, individuals carry this novel SNV. Western blot analysis show reduced levels of TCIRG1 protein in affected individuals, compared to healthy controls. Two unrelated patients with SCN, identified by independent investigators, are heterozygous for different, rare, highly conserved, coding variants in TCIRG1.
Journal of Pediatric Genetics · 2018 · 2 citations · open access
Description of an ELANE Mutation in a Girl with Severe Congenital Neutropenia: A Paradigm of Targeted Genetic Screening Based on Clinical Findings
AbstractAbstract We describe the case of a 5-year-old girl with severe congenital neutropenia presenting with recurrent skin and respiratory infections. Sequence analysis of ELANE and HAX1 genes identified a mutation in heterozygous state in exon 2 of the ELANE gene: c.157C > G (p.His53Asp), not previously described in the literature at the exon coding level. Given the autosomal dominant inheritance and the location of the mutation within a “hotspot,” this mutation was considered as clinically relevant. ELANE should be screened in patients with congenital neutropenia of no obvious etiology. A detailed medical history and clinical evaluation can prevent unnecessary investigations allowing for a targeted diagnostic strategy.
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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