DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Potocki-Shaffer syndrome — 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 modulePotocki-Shaffer syndrome 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 potocki-shaffer 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
PHD finger protein 21A (PHF21A) — PHF21A 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 2PUY · 1.43 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
In Potocki-Shaffer syndrome, the full phenotypic spectrum is seen when deletions are at least 2.1 Mb in size at 11p11.2. Fewer than 40 to 50 individuals have been reported in the literature. The syndrome is characterised by craniofacial abnormalities, moderate-to-severe developmental delay and intellectual disability, multiple exostoses, and biparietal foramina. One study of six patients identified for the first time an association with sensorineural hearing loss and autistic behaviours. A separate case report of an adult woman with a 2.3 Mb deletion described multiple exostoses, severe mental retardation, epilepsy and facial dysmorphisms; her diagnosis was only suggested when she was examined at adult age, illustrating that rare diseases frequently remain undiagnosed until adulthood.
A 2012 report described a boy with a 137 kb deletion within the PSS interval, resulting in haploinsufficiency for all or portions of six OMIM genes: SLC35C1, CRY2, MAPK8IP1, PEX16, GYLTL1B, and PHF21A. He presented at 13 months with developmental delay, hypotonia, subtle dysmorphic features, and neurobehavioural abnormalities. The authors identified this small deletion as a critical region sufficient to cause hypotonia in this syndrome. A 2015 study refined the candidate gene region to five genes and, by excluding SLC35C1 and CRY2, corroborated a role for PHF21A in developmental delay and craniofacial anomalies. That patient had partial PSS phenotypes including global developmental delay, craniofacial anomalies, minor limb anomalies, and micropenis.
A 2023 study analysed 13 individuals with constitutional PHF21A variants. Among those with data recorded, postnatal overgrowth was reported in 5 out of 6 (83%). All had intellectual disability and behavioural issues. Frequent associations included postnatal hypotonia (7/11, 64%) and at least one afebrile seizure episode (6/12, 50%). No recognisable facial gestalt was associated, but subtle dysmorphic features such as a tall broad forehead, broad nasal tip, anteverted nares and full cheeks were shared among some individuals. The authors suggested PHF21A might be considered a new member of the overgrowth-intellectual disability syndrome family.
What is still missing is a clear understanding of the full range of deletion sizes and their precise phenotypic correlations, given the small number of reported cases. No drug treatment is mentioned in any of these abstracts. There is no trial design, no patient stratification strategy, and no funding directed at a pharmacological intervention for this syndrome.
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 · 2015 · 48 citations
A microdeletion encompassing <i>PHF21A</i> in an individual with global developmental delay and craniofacial anomalies
AbstractIn Potocki-Shaffer syndrome (PSS), the full phenotypic spectrum is manifested when deletions are at least 2.1 Mb in size at 11p11.2. The PSS-associated genes EXT2 and ALX4, together with PHF21A, all map to this region flanked by markers D11S1393 and D11S1319. Being proximal to EXT2 and ALX4, a 1.1 Mb region containing 12 annotated genes had been identified by deletion mapping to explain PSS phenotypes except multiple exostoses and parietal foramina. Here, we report a male patient with partial PSS phenotypes including global developmental delay, craniofacial anomalies, minor limb anomalies, and micropenis. Using microarray, qPCR, RT-qPCR, and Western blot analyses, we refined the candidate gene region, which harbors five genes, by excluding two genes, SLC35C1 and CRY2, which resulted in a corroborating role of PHF21A in developmental delay and craniofacial anomalies. This microdeletion contains the least number of genes at 11p11.2 reported to date. Additionally, we also discuss the phenotypes observed in our patient with respect to those of published cases of microdeletions across the Potocki-Shaffer interval.
American Journal of Medical Genetics Part A · 2010 · 38 citations
Potocki–Shaffer syndrome: Comprehensive clinical assessment, review of the literature, and proposals for medical management
AbstractPotocki-Shaffer syndrome is a rare contiguous gene deletion syndrome due to haploinsufficiency of the 11p11.2p12 region and is characterized by craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses, and biparietal foramina. In this study, six patients with the Potocki-Shaffer syndrome were identified and evaluated using a multidisciplinary protocol that included assessments by a geneticist, ophthalmologist, otolaryngologist, orthopedist, nephrologist, audiologist, and neuropsychologist. Diagnostic studies included skeletal survey, magnetic resonance imaging of the brain, renal ultrasound, complete blood count, comprehensive metabolic panel, thyroid studies, and urinalysis. Using array comparative genomic hybridization, we further characterized the deletion in five of these patients. The results of these evaluations were combined with a comprehensive review of reported cases. Our data highlight the characteristic facial features, biparietal foramina, moderate-to-severe developmental delay and intellectual disability, myopia and strabismus, and multiple exostoses seen with this disorder. We also identify for the first time an association of Potocki-Shaffer syndrome with sensorineural hearing loss and autistic behaviors. Finally, we provide recommendations for the health maintenance of patients with Potocki-Shaffer syndrome.
American Journal of Medical Genetics Part A · 2012 · 11 citations
A 137‐kb deletion within the Potocki–Shaffer syndrome interval on chromosome 11p11.2 associated with developmental delay and hypotonia
AbstractPotocki-Shaffer syndrome (PSS) is a rare disorder caused by haploinsufficiency of genes located on the proximal short arm of chromosome 11 (11p11.2p12). Classic features include biparietal foramina, multiple exostoses, profound hypotonia, dysmorphic features, and developmental delay/intellectual disability. Fewer than 40 individuals with PSS have been reported, with variable clinical presentations due in part to disparity in deletion sizes. We report on a boy who presented for initial evaluation at age 13 months because of a history of developmental delay, hypotonia, subtle dysmorphic features, and neurobehavioral abnormalities. SNP microarray analysis identified a 137 kb deletion at 11p11.2, which maps within the classically defined PSS interval. This deletion results in haploinsufficiency for all or portions of six OMIM genes: SLC35C1, CRY2, MAPK8IP1, PEX16, GYLTL1B, and PHF21A. Recently, translocations interrupting PHF21A have been associated with intellectual disability and craniofacial anomalies similar to those seen in PSS. The identification of this small deletion in a child with developmental delay and hypotonia provides further evidence for the genetic basis of developmental disability and identifies a critical region sufficient to cause hypotonia in this syndrome. Additionally, this case illustrates the utility of high resolution genomic approaches in correlating clinical phenotypes with specific genes in contiguous gene deletion syndromes.
Molecular Syndromology · 2011 · 7 citations · open access
Delayed Diagnosis of Potocki-Shaffer Syndrome in a Woman with Multiple Exostoses and Mental Retardation
AbstractWe describe the case of an adult patient affected by multiple exostoses, severe mental retardation, epilepsy and facial dysmorphisms with a deletion of ∼2.3 Mb on chromosome 11p11.21, correlated to Potocki-Shaffer syndrome (PSS). PSS is a rare contiguous gene deletion syndrome, mainly characterized by multiple exostoses and bilateral parietal foramina. Mental retardation and craniofacial dysmorphisms have often been reported, too. Although the patient showed many signs of PSS since early childhood, the diagnosis was suggested only when we examined her at adult age. This case highlights how frequently rare diseases remain undiagnosed till adulthood and is an excellent example of the need for a timely and correct diagnosis.
BMC Research Notes · 2015 · 6 citations · open access
17p11.2 and Xq28 duplication detected in a girl diagnosed with Potocki–Lupski syndrome
AbstractBACKGROUND: Potocki-Lupski syndrome is a microduplication syndrome associated with duplication at 17p11.2. Features include facial dysmorphism, moderate to mild cognitive impairment and behavioural abnormalities including autism spectrum disorders. CASE PRESENTATION: We describe a patient from Sri Lanka that was referred for genetic assessment at 4 years of age due to subtle facial dysmorphism and expressive language impairment. She was diagnosed with Potocki-Lupski syndrome through multiplex ligation probe amplification. She carried two duplications; one in 17p11.2 consistent with Potocki-Lupski, and one in Xq including the region for X-linked intellectual disability. CONCLUSION: Despite the absence of expected behavioural symptoms, many features of this patient are in accordance with Potocki-Lupski syndrome. This is the first diagnosed patient in Sri Lanka.
Clinical Dysmorphology · 2023 · 5 citations · open access
The PHF21A neurodevelopmental disorder: an evaluation of clinical data from 13 patients
AbstractPotocki-Shaffer syndrome (PSS) is a rare neurodevelopmental disorder caused by deletions involving the 11p11.2-p12 region, encompassing the plant homeodomain finger protein 21A (PHF21A) gene. PHF21A has an important role in epigenetic regulation and PHF21A variants have previously been associated with a specific disorder that, whilst sharing some features of PSS, has notable differences. This study aims to expand the phenotype, particularly in relation to overgrowth, associated with PHF21A variants. Analysis of phenotypic data was undertaken on 13 individuals with PHF21A constitutional variants including four individuals described in the current series. Of those individuals where data were recorded, postnatal overgrowth was reported in 5/6 (83%). In addition, all had both an intellectual disability and behavioural issues. Frequent associations included postnatal hypotonia (7/11, 64%); and at least one afebrile seizure episode (6/12, 50%). Although a recognizable facial gestalt was not associated, subtle dysmorphic features were shared amongst some individuals and included a tall broad forehead, broad nasal tip, anteverted nares and full cheeks. We provide further insight into the emerging neurodevelopmental syndrome associated with PHF21A disruption. We present some evidence that PHF21A might be considered a new member of the overgrowth-intellectual disability syndrome (OGID) family.
AbstractThe Potocki-Shaffer syndrome (OMIM #601224) is a rare contiguous gene syndrome resulting from the microdeletion on chromosome 11p11.2p12. Patients show distinctive craniofacial abnormalities, a frequently generally retarded development, multiple exostoses, bifrontal foramina and genitourinary abnormalities. Less than fifty cases have been described in literature worldwide.
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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