DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for autosomal recessive disease — 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 recessive disease 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 recessive disease 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
calpain 3 (CAPN3) — CAPN3 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6BDT · 2.3 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
In a 1994 review of autosomal recessive osteopetrosis, which is relatively common in Saudi Arabia due to consanguineous marriage, the disease is attributed to a lysosomal defect of the osteoclast. It presents with increased bone density, fractures, and cranial nerve palsies. The severe (malignant) form in children is treated with bone marrow transplantation, stated as the treatment of choice; no survival or response rates are given.
A 2021 case series of two siblings with pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) from a consanguineous Iranian-Azeri family identified a novel homozygous p.Ser242Gly variant in MEFV. The children, aged 5 and 2.5 years, had recurrent rash, gastrointestinal involvement, and intussusception. Treatment with colchicine (1 mg/d) and low-dose prednisolone (2.5 mg every other day) was started, and the patients responded well. The authors describe this as a successful genotype-guided treatment, but the sample is two patients, and no long-term outcomes are reported.
A 2015 study used whole-genome sequencing in a single Charolais calf with junctional epidermolysis bullosa from a consanguineous herd. It identified a homozygous deletion of exons 17 to 23 in ITGB4, a gene associated with the same defect in humans. Genotyping of a second case and six parents showed perfect association with the mutation. Screening of 6870 Charolais cattle found 44 heterozygotes for a shared haplotype, but none of 16 animals genotyped for the deletion carried it, suggesting a recent origin. No treatment is discussed.
A 2016 report describes recessive congenital methemoglobinemia type I in a mother and daughter, with an Arg50Gln mutation not previously reported in the Turkish population. This is an observation of inheritance in immediate generations, with no treatment or outcome data.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Annals of Saudi Medicine · 1994 · 22 citations · open access
Autosomal Recessive Osteopetrosis
AbstractOsteopetrosis is a genetic disease that is relatively common in Saudi Arabia because of the high rate of consanguineous marriages. It is thought to be due to a lysosomal defect of the osteoclast. It is characterized by marked increase in bone density, frequent fractures and cranial nerve palsies. It is transmitted as an autosomal recessive or autosomal dominant. The autosomal recessive type is common in children and has three forms: severe (malignant), mild (intermediate), and the one associated with cerebral calcification and renal tubular acidosis. Bone marrow transplantation is the treatment of choice for the severe (malignant) type.
JAMA Dermatology · 2021 · 15 citations · open access
Homozygous <i>MEFV</i> Gene Variant and Pyrin-Associated Autoinflammation With Neutrophilic Dermatosis
AbstractIMPORTANCE: Pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) is a monogenic autoinflammatory disorder with autosomal dominant inheritance and has been associated with monoallelic p.Ser242Arg and p.Glu244Lys variations in the MEFV gene. This dermatosis shares clinical features and pathogenesis with familial Mediterranean fever, although it is a clinically distinct entity. OBJECTIVE: To identify the genetic basis of PAAND in a consanguineous family with 2 affected children and to prescribe an effective genotype-guided treatment. DESIGN, SETTING, AND PARTICIPANTS: This case series study examined 2 siblings who presented with clinical features of PAAND. We sought the genetic basis of this disease with trio whole exome sequencing (trio-WES). Genome-wide homozygosity mapping provided additional evidence for causality of a sequence variant identified by trio-WES. MAIN OUTCOMES AND MEASURES: Association of a biallelic MEFV variation with a new form of autosomal recessive PAAND was documented by genetic analysis. Response to treatment with colchicine and a low-dose steroid was assessed clinically and experimentally. RESULTS: Two siblings, a girl (proband; age 5 years) and a boy (age 2.5 years) of Iranian-Azeri ancestry born to first-cousin consanguineous parents presented with clinical features of PAAND-recurrent episodes of maculopapular and pustular rash, gastrointestinal involvement resembling inflammatory bowel disease, and intussusception with generalized mesenteric lymphadenitis. A trio-WES test detected a previously unreported homozygous missense variation, p.Ser242Gly, in both patients' MEFV gene. Genome-wide homozygosity mapping revealed shared regions of homozygosity in the patients' DNA, including 1 on chromosome 16 harboring MEFV. Whole transcriptome sequencing by RNA-sequencing revealed that the variant MEFV transcript, among the inflammasome-associated transcripts, was most upregulated, and the cell-cell receptor interaction and innate immune system pathways were most positively enriched. Under the guidance of MEFV genotype, treatment with colchicine (1 mg/d) and low-dose prednisolone (2.5 mg every other day) was started, and the patients responded well. CONCLUSIONS AND RELEVANCE: This case series study demonstrated successful genotype-guided treatment with colchicine and low-dose prednisolone, a low-cost therapeutic option with minimal adverse effects, in patients with a novel form of autosomal recessive PAAND. This case report examines the genetic basis of PAAND in a consanguineous family with 2 affected children and seeks to prescribe an effective genotype-guided treatment.
Whole-genome sequencing identifies a homozygous deletion encompassing exons 17 to 23 of the integrin beta 4 gene in a Charolais calf with junctional epidermolysis bullosa
AbstractBACKGROUND: Since 2010, four Charolais calves with a congenital mechanobullous skin disorder that were born in the same herd from consanguineous matings were reported to us. Clinical and histopathological examination revealed lesions that are compatible with junctional epidermolysis bullosa (JEB). RESULTS: Fifty-four extended regions of homozygosity (>1 Mb) were identified after analysing the whole-genome sequencing (WGS) data from the only case available for DNA sampling at the beginning of the study. Filtering of variants located in these regions for (i) homozygous polymorphisms observed in the WGS data from eight healthy Charolais animals and (ii) homozygous or heterozygous polymorphisms found in the genomes of 234 animals from different breeds did not reveal any deleterious candidate SNPs (single nucleotide polymorphisms) or small indels. Subsequent screening for structural variants in candidate genes located in the same regions identified a homozygous deletion that includes exons 17 to 23 of the integrin beta 4 (ITGB4), a gene that was previously associated with the same defect in humans. Genotyping of a second case and of six parents of affected calves (two sires and four dams) revealed a perfect association between this mutation and the assumed genotypes of the individuals. Mining of Illumina BovineSNP50 Beadchip genotyping data from 6870 Charolais cattle detected only 44 heterozygous animals for a 5.6-Mb haplotype around ITGB4 that was shared with the carriers of the mutation. Interestingly, none of the 16 animals genotyped for the deletion carried the mutation, which suggests a rather recent origin for the mutation. CONCLUSIONS: In conclusion, we successfully identified the causative mutation for a very rare autosomal recessive mutation with only one case by exploiting the most recent DNA sequencing technologies.
The Turkish Journal of Pediatrics · 2016 · 10 citations · open access
Recessive congenital methemoglobinemia in immediate generations
AbstractWe report herein on our observation of recessive congenital methemoglobinemia (type I), an autosomal recessive disorder, in immediate generations (in a mother and her daughter). Molecular analysis revealed a mechanism of inheritance not reported previously, despite the high probability of occurrence in autosomal recessive disorders. This report is also the first publication describing an extremely rare mutation (Arg50Gln) causing this disorder in the Turkish population.
Archives of Disease in Childhood · 2017 · 5 citations
Fifteen years of genetic testing from a London developmental clinic
AbstractOBJECTIVE: To evaluate genetic disease among children referred to a community paediatric clinic. DESIGN: Retrospective cohort study. SETTING: Community paediatric clinic, Tower Hamlets, London. PATIENTS: All patients seen for first time in the Child Development Team (CDT) clinic between 1999 and 2013. INTERVENTIONS: Clinical notes were reviewed. Genetic test results were obtained. Exploratory Excel analysis was performed. Patients without an identified genetic disorder were labelled 'more likely genetic cause' if they had at least two out of three risk factors: developmental delay, congenital abnormality or parental consanguinity, and 'unlikely genetic cause' if they had one or no risk factors, or an obvious alternative cause. MAIN OUTCOME MEASURES: Prevalence of genetic diagnoses and parental consanguinity, undertaking of genetic tests, predicted likelihood of a genetic cause among unsolved patients. RESULTS: 749 patients were included. 404 (53.9%) had undergone genetic testing and 158 of those tested (39.1%) had a confirmed genetic diagnosis. Parental relatedness was documented in 461 patients, of which 128 (27.8%) had first-cousin parents. The number of patients undergoing genetic testing increased over time. Aneuploidies and syndromic/Mendelian disorders were most common. Of the 591 patients without a genetic diagnosis, 29.9% were classified 'more likely genetic cause'. Patients with consanguineous parents were significantly more likely to have a diagnosed genetic disorder than those with non-consanguineous parents (43/128 vs 72/333), particularly an autosomal recessive condition (27/43 vs 6/72). CONCLUSIONS: Genetic disease was common and genetic testing is important in evaluating children in this clinic. Consanguinity increases the likelihood of autosomal recessive disease.
American Journal of Ophthalmology Case Reports · 2022 · 2 citations · open access
Alström syndrome caused by maternal uniparental disomy
AbstractPurpose: To describe a case of Alström syndrome arising from maternal uniparental disomy. Observations: c.2141_2141del (p.Ser714Tyrfs*6), that was only found in his mother and not his father. In contrast to the usual autosomal recessive inheritance pattern in which a child inherits a variant from each parent, multi-step genetic testing of the child and both parents confirmed uniparental disomy as the mechanism of inheritance. Conclusions and Importance: Confirmation of uniparental disomy in autosomal recessive disorders allows for parental assurance that future offspring will be unaffected.
Pediatric Rheumatology · 2014 · 1 citations · open access
Identification of a novel monogenic autoinflammatory disease due to mutation in a mitochondrial chaperone protein in a single kindred, and cure with allogeneic haematopoietic stem cell transplantation
AbstractThe monogenic autoinflammatory syndromes are characterised by seemingly unprovoked inflammation which derives from a disruption of innate immunity. Novel as yet undefined autosomal recessive syndromes are increasingly recognised in consanguineous families. This type of family is ideal for genetic mapping.
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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