DeCure for Silverman-Handmaker type dyssegmental dysplasia
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Silverman-Handmaker type dyssegmental dysplasia — 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 moduleSilverman-Handmaker type dyssegmental dysplasia 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 silverman-handmaker type dyssegmental dysplasia 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
heparan sulfate proteoglycan 2 (HSPG2) — HSPG2 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 3SH4 · 1.5 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Dyssegmental dysplasia Silverman-Handmaker type is an extremely rare skeletal dysplasia caused by null mutations in the perlecan gene (HSPG2). Fewer than forty cases have been reported in the literature. A 2018 report described a dizygotic twin pregnancy from consanguineous parents in which one twin presented prenatally with severe micromelia, limb bowing and scoliosis, and was found postnatally to carry a novel homozygous variant in HSPG2 (c.4029+1G>A). That report was described as only the seventh molecularly confirmed case of DDSH.
A 2020 report described the ninth genetically diagnosed patient, a male abortus at 15 weeks whose parents were not consanguineous. This case presented hydrops fetalis in the first trimester, which had not been reported previously in DDSH. Trio whole-exome sequencing identified a homozygous missense variation in HSPG2 (c.3197G>A, p.R1066Q). In-silico predictions were mixed: most algorithms predicted damaging or disease-causing effects, but some (MutationAssessor, LRT, FATHMM, MetaSVM, MetaLR) predicted tolerated, medium, or neutral effects. The allele frequency in public databases was 0.04–0.22%. The authors noted that the homozygous mutation may imply a founder effect in the Taiwanese population.
A 2022 report identified two novel heterozygous mutations in HSPG2 (c.6001dupC, p.R2001pfs*19 and c.11207G>A, p.R373Q) in a fetus from a pregnancy with a previous history of short limb malformation. The diagnosis was confirmed by next-generation sequencing-based deep panel sequencing. This was described as the first report to prenatally identify these particular novel mutations.
No treatment or intervention for DDSH is described in any of these abstracts. The condition is consistently described as lethal. What remains missing is any systematic effort to understand the natural history across more than isolated case reports, any funding for functional studies of the identified variants, and any prospect of prenatal or postnatal therapy given the extreme rarity of the disorder.
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 · 1987 · 56 citations
Dyssegmental dysplasias: Clinical, radiographic, and morphologic evidence of heterogeneity
AbstractThe dyssegmental dysplasias are lethal forms of neonatal short-limbed dwarfism in which vertebral segmentation defects and short, thick, bowed long bones are the prominent radiographic features. Clinically, unusual facies, short neck, narrow thorax, cleft palate, and reduced joint mobility are commonly seen. To date, 18 cases of dyssegmental dysplasia have been reported. Reports of three pairs of affected sibs suggest autosomal recessive inheritance. We have studied eight additional cases of dyssegmental dysplasia, including one pair of affected sibs. Clinical, radiographic, and histologic examination of these new cases and review of the literature demonstrates the presence of at least two distinct forms of dyssegmental dysplasia. The milder form, "dyssegmental dysplasia, type Rolland-Desbuquois," is characterized clinically by frequent survival beyond the newborn period and by distinct radiographic changes resembling Kniest dysplasia. The severe form, "dyssegmental dysplasia, type Silverman-Handmarker," is characterized by stillbirth or death within the first few days of life and by distinct and more severe radiographic changes. In addition, we have demonstrated chondro-osseous morphologic differences between the two disorders by light and electron microscopy. We conclude that there are at least two forms of dyssegmental dysplasia, each autosomal recessive, which can be delineated on clinical, radiographic and morphologic grounds.
Molecular Genetics & Genomic Medicine · 2018 · 7 citations · open access
Dyssegmental dysplasia, Silverman‐Handmaker type: A challenging antenatal diagnosis in a dizygotic twin pregnancy
AbstractBACKGROUND: Dyssegmental dysplasia Silverman-Handmaker (DDSH; MIM 224410) type is an extremely rare skeletal dysplasia caused by functional null mutations in the perlecan gene. Less than forty cases are reported in the literature, of which only four were prenatally detected. METHODS: We report on a dizygotic twin pregnancy from consanguineous parents for which one of the twins presented prenatally with severe micromelia, limb bowing and scoliosis, and postnatally with clinical and radiological features compatible with a diagnosis of dyssegmental dysplasia. Molecular studies were undertaken to confirm the clinical diagnosis of DDSH. RESULTS: Molecular analysis results revealed a novel homozygous variant in the HSPG2 gene (MIM 142461), NM_005529.6(HSPG2):c.4029 + 1G>A, consistent with a diagnosis of DDSH. CONCLUSION: To the best of our knowledge, the current report is only the seventh molecularly confirmed case of DDSH.
Ultrasound in Obstetrics and Gynecology · 2020 · 5 citations · open access
Hydrops in first trimester as unreported prenatal finding of dyssegmental dysplasia confirmed by exome sequencing
AbstractDyssegmental dysplasia, Silverman–Handmaker type (DDSH) (OMIM: 224410), is an extremely rare and lethal form of skeletal dysplasia (SD) characterized by vertebral disorganization (anisospondyly), limb deformities (severely short limbs, joint contracture and talipes equinovarus), and an abnormal facial appearance (flat face or micrognathia)1. Null mutations in the heparin sulfate proteoglycan 2 (HSPG2) (OMIM: *142461) gene are associated with DDSH, but, until now, only eight molecularly confirmed cases have been reported2. Here, we report the ninth case of DDSH, which presented hydrops fetalis in the first trimester and was confirmed genetically by trio-based whole-exome sequencing (trio-WES). A 27-year-old woman, gravida 2 para 0 (one previous miscarriage), visited our hospital at 12 + 6 weeks' gestation due to a fetal anomaly. The woman reported that she was not in a consanguineous marriage and she underwent regular antenatal checkups. She presented microcytic anemia but her husband was normocytic with normal hemoglobin level. First-trimester Down screening revealed a low risk. At the visit, the anomaly scan showed scalp edema (Figure 1a) with decreasing limb mobility. Common infectious etiologies of fetal hydrops were excluded by the TORCH survey. Chorionic villus sampling was then performed for genetic testing. Interphase fluorescence in-situ hybridization of chorionic villi revealed a male combination of sex chromosomes (XY) and disomy for chromosomes 13, 18 and 21. Conventional karyotyping of cultured villi failed, while array comparative genomic hybridization with CytoScan DNA chip (Agilent customer design ID 040427, Changhua Christian Hospital, Changhua, Taiwan) identified one copy of deletion in the HBA gene (arr[hg19] 16p13.3(217198_231179) × 1). Genes, including PTPN11 and ITGA9, that are associated with lymphangiomatosis and chylothorax3 were also sequenced but no variations were detected. At 14 + 4 weeks, hydrops fetalis, thick placenta and severe micromelia had developed (Figure 1b,c). After non-directive counseling, the couple opted for termination of pregnancy. A male abortus weighing 55 g and of 12 cm in length was delivered vaginally at 15 weeks. The abortus showed low-set ears, micrognathia and severe micromelia with bilateral club hands and talipes equinovarus (Figure 1d). Trio-WES was performed to determine the underlying cause of the pathology (Appendix S1). A total of 92 911 variations were identified, including 82 191 single-nucleotide variations and 10 720 small insertions/deletions. Initially, analysis was targeted at a gene set (504 genes) associated with hydrops and kidney disorder. However, no disease-related variations were detected. We then shifted our focus to a comprehensive gene panel (317 genes) involved in the etiology of SD based on the finding of micromelia. Twenty-two variations on SD genes were found. An autosomal recessive or X-linked recessive inheritance mode was hypothesized in this family because the couple did not manifest the relevant phenotype and as the abortus was male. As a result, only one biparental-origin variation (NM_005529.7:c.3197G>A(p.R1066Q), rs537872144) in the HSPG2 gene was detected, following an autosomal recessive mode of inheritance (Figure 2a,b). The variation is located in a laminin IVA protein domain (PROSITE entry PS51115), resulting in the amino acid in position 1066 changing from a positive-charged arginine (R) to a neutral-charged glutamine (Q). Cross-species conservation analysis of HSPG2 amino acids among humans and 27 other mammal species showed high cross-species conservation of the p. 1066 arginine residue (Figure 2c). Prediction analysis of the variation's impact on protein function showed damaging/disease-causing/deleterious effects in the algorithms of SIFT, Polyphen-2 HVAR, MutationTaster, PROVEAN, fathmm-MKL, GERP++, PhyloP 100way and SiPhy 29way, and tolerated/medium/neutral effects in the algorithms of MutationAssessor, LRT, FATHMM, MetaSVM and MetaLR (Table S1). Most of the algorithms predicted a strong effect of the c.3197G>A mutation in the HSPG2 protein, providing evidence to support the deleterious nature of the mutation. The allele frequency of this variation was 0.04–0.22% in public databases (gnomAD-exomes Asian, gnomAD-exomes Global, ExAC Asian and ExAC Global) (Table S1). Sanger sequencing confirmed the homozygous and heterozygous statuses of the HSPG2 c.3197G>A(p.R1066Q) variation in the abortus and parents, respectively. SD is a group of disorders with genetic heterogeneity and various manifestations that render making a definitive diagnosis challenging. Up to now, more than 450 SD diseases classified into 42 groups with a variety of inheritance patterns have been reported4. DDSH belongs to the HSPG2 group4 and shares features with other SD diseases (Table S2). Recently, due to the advantages of high-throughput DNA sequencing, it has become possible to achieve more comprehensive genetic analysis that improves the discovery of the underlying cause of diseases with genetic heterogeneity. Functional null mutation in the HSPG2 gene, which encodes the HSPG2 protein, has been recognized as the cause of DDSH, by completely preventing HSPG2 secretion into the various extracellular matrices. Among the eight previously reported DDSH cases with a homozygous or compound heterozygous mutation in the HSPG2 gene, most showed the fetal features of micromelia, encephalocele, narrow chest and spine disorganization, of which the earliest was detected at 13 weeks5. Our case represents the ninth genetically diagnosed patient in which DDSH resulted from a homozygous missense variation (c.3197G>A(p.R1066Q)) in the HSPG2 gene. In particular, our case showed hydrops in the first trimester, which has not been reported previously in DDSH and thus expands the phenotypic spectrum of this disorder. This report describes the prenatal findings of the rare disease of DDSH and shows that the application of WES to heterogeneous diseases, such as SD, enables the discovery of underlying genetic defects. Of note, the homozygous HSPG2 mutation detected may imply a founder effect in the Taiwanese population, which we noted previously in several monogenic diseases such as autosomal recessive renal tubular dysgenesis, osteogenesis imperfecta Type IX and aromatic L-amino acid decarboxylase deficiency6. This study was partly supported by research grants from Ministry of Science and Technology, Executive Yuan, Taiwan (grant number MOST 107-2314-B-371-009-MY3) and Changhua Christian Hospital, Taiwan (grant number 106-CCH-ICO-152 and 108-CCH-IRP-101). Data available on request from the authors. Appendix S1 Supplementary methods for whole-exome sequencing and variation analysis Table S1 In-silico predictions of functional effects and allele frequency of the HSPG2 c.3197G>A(p.R1066Q) variation detected in this study Table S2 Shared features of dyssegmental dysplasia, Silverman–Handmaker type (DDSH), with other skeletal dysplasia (SD) diseases that have different causative genes and diverse inheritance patterns Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Clinical and Experimental Obstetrics & Gynecology · 2022 · 1 citations · open access
Prenatal identification of novel HSPG2 variants associated with dyssegmental dysplasia Silverman-Handmaker type
AbstractBackground: We aimed to analyze mutations of the pathogenic gene in dyssegmental dysplasia Silverman-Handmaker (DDSH) type associated with the Heparin sulfate proteoglycan 2 (HSPG2) gene. Case: Prenatal testing for genetic mutations associated with fetal DDSH were performed on a pregnant woman with previous history of carrying a fetus with short limb malformation at the 17th week of gestation. DNA was extracted from amniotic fluid and next-generation sequencing-based deep panel sequencing was performed on the Illumina NextSeq platform to identify possible causative mutations of DDSH. Results: Two novel heterozygous mutations in HSPG2 gene, c.6001dupC (p. R2001pfs*19) and c.11207G>A (p. R373Q), were identified and associated with the DDSH diagnosis. Conclusion: This is the first report to prenatally identify novel mutations in HSPG2 that confirms a DDSH diagnosis.
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.
