DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Perlman syndrome — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease modulePerlman syndrome maps to a 1-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 perlman 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
DIS3 exosome endoribonuclease and 3'-5' exoribonuclease (DIS3) — DIS3 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 anpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6D6Q · 3.45 Å · ligand PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER (ANP). Experimental structure, not a prediction.
What the evidence adds up to
Perlman syndrome is a rare autosomal recessive overgrowth disorder caused by mutations in the DIS3L2 gene. The syndrome presents with a severe phenotype that usually results in early postnatal death. Overgrowth affects internal organs including the liver, pancreas, and especially the kidneys, with histological findings of focal hamartomas and nephroblastomatosis. These dysplasias predispose to Wilms tumour, a very common occurrence in the syndrome. More than 30 cases have been reported in the literature with clinical features of the syndrome, but very few cases have had the underlying genetic defect identified. The condition seems to be very rare, and mild cases, if any exist, may go undiagnosed.
A 2017 report described a 6-year-old Japanese female patient with Perlman syndrome who survived long term. She carried novel compound heterozygous missense mutations in the RNB domain of DIS3L2 (c.[367-2A>G];[1328T>A]). Most previously reported DIS3L2 mutations have been homozygous deletions of exon 6 or exon 9, which would cause loss of both RNA binding and degradation activity. The authors proposed that the long-term survival in this patient was due to one missense mutation (c.1328T>A, p.Met443Lys) retaining RNA binding in the cold-shock domains and S1 domain, and allowing partial RNA degradation. They suggested that if partial exonuclease function remains in at least one allele, long-term survival may be possible.
A 2022 study reported a child with Perlman syndrome who harboured compound heterozygous variants of DIS3L2: c.2109delC and c.1829.c.1830insC, inherited from the mother and father respectively. Both variants were predicted to be pathogenic according to ACMG guidelines. A 2020 report described a neonate with typical clinical features of Perlman syndrome and a deletion of the DIS3L2 gene confirmed by array comparative genomic hybridization. The clinical features of Perlman syndrome overlap with Beckwith-Wiedemann syndrome, prune belly syndrome, and Simpson-Golabi-Behmel syndrome.
What is still missing is a clear understanding of the full spectrum of DIS3L2 mutations and their genotype-phenotype correlation, as the causal mutation was discovered only recently and it is not known if DIS3L2 is the only causal gene. Further studies of patients with proven DIS3L2 mutations are needed. There is no established treatment or clinical trial for Perlman syndrome, and the rarity of the condition makes patient stratification and trial design difficult.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
American Journal of Medical Genetics Part A · 2017 · 11 citations
Long term survival of a patient with Perlman syndrome due to novel compound heterozygous missense mutations in RNB domain of <i>DIS3L2</i>
AbstractPerlman syndrome is a rare overgrowth syndrome characterized by polyhydramnios, macrosomia, distinctive facial appearance, renal dysplasia, and a predisposition to Wilms' tumor. The syndrome is often associated with a high neonatal mortality rate and there are few reports of long-term survivors. We studied a 6-year-old Japanese female patient, who was diagnosed with Perlman syndrome, with novel compound heterozygous mutations in DIS3L2 (c.[367-2A > G];[1328T > A]), who has survived long term. Most reported DIS3L2 mutations have been the homozygous deletion of exon 6 or exon 9, and these mutations would certainly have caused the loss of both RNA binding and degradation activity. We have identified new compound heterozygous mutations in the DIS3L2 of this long-term survivor of Perlman syndrome. The reason our patient has survived long-term would be a missense mutation (c.1328 T > A, p.Met443Lys) having retained RNA binding in both the cold-shock domains and the S1 domain, and through partial RNA degradation. If partial exonuclease functions remain in at least one allele, long-term survival may be possible. Further studies of Perlman syndrome patients with proven DIS3L2 mutations are needed to clarify genotype-phenotype correlation.
[Clinical features and genetic analysis of a case with Perlman syndrome due to variant of DIS3L2 gene].
AbstractOBJECTIVE: To analyze the clinical phenotype and genetic characteristics of a child with Perlman syndrome. METHODS: Genomic DNA was extracted from peripheral blood samples from the patient and her parents. Whole exome sequencing (WES) was carried out to detect potential variant in the proband. Candidate variant was verified by Sanger sequencing. The pathogenicity of candidate variants was evaluated according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). RESULTS: The results of WES showed that the proband has harbored compound heterozygous variants of the DIS3L2 gene, namely c.2109delC and c.1829.c.1830insC, which were respectively inherited from her mother and father. The results were confirmed by Sanger sequencing. Based on the ACMG guidelines, the two novel variants were both predicted to be pathogenic (PVS1+PS2+PM2). CONCLUSION: The compound heterozygous variants of the DIS3L2 gene probably underlay the Perlman syndrome in this patient. Above finding has enriched the spectrum of DIS3L2 gene mutations.
Oxford University Press eBooks · 2019 · 0 citations
Perlman Syndrome
AbstractThis chapter describes Perlman syndrome, which is an autosomal recessive overgrowth syndrome that presents with a severe phenotype, usually resulting in early postnatal death. Overgrowth is extended to the internal organs, liver, pancreas, and especially kidneys, with histologic findings of focal hamartomas and nephroblastomatosis. These dysplasias predispose to the development of Wilms tumor, a very common occurrence in Perlman syndrome. The condition seems to be very rare, even though mild cases, if any exist, may go undiagnosed. The causal mutation affecting the <italic>DIS3L2</italic> gene was discovered only recently and it is not known if this is the only causal gene.
Research and Reports in Neonatology · 2020 · 0 citations · open access
<p>Perlman Syndrome with Deletion of <em>DIS3L2</em> Gene</p>
AbstractAbstract: Perlman syndrome is a rare genetic disorder with autosomal recessive inheritance. It is caused by deletion of the DIS3L2 gene on the long arm of chromosome 2. Though more than 30 cases have been reported in the literature with clinical features of the syndrome, very few cases have identified underlying genetic defects. The clinical features of Perlman syndrome have similarities with those of Beckwith–Wiedemann syndrome (BWS), prune belly syndrome (PBS) and Simpson–Golabi–Behmel syndrome (SGBS1). Affected patients have macrosomia, dysmorphic features, hypotonia, laxity of abdominal wall, cryptorchidism, renal anomalies and risk of development of Wilm’s tumour. Here we report a neonate with typical clinical features of Perlman syndrome, with deletion of DIS3L2 gene confirmed by array comparative genomic hybridization (aCGH). Keywords: DIS3L2 , Perlman syndrome, prune belly syndrome, Wilm’s tumour
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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