No approved-drug candidate for intellectual disability-facial dysmorphism syndrome due to setd5 haploinsufficiency 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.
The abstracts provided do not contain any drug repurposing data for SETD5 haploinsufficiency. One 2021 paper describes two patients with pathogenic SETD5 variants and bone fragility, a previously unreported association. Patient 1, a 14-year-old male with a heterozygous c.1381_1388del variant, had multiple thoracic vertebral crush fractures after a minor fall. After 10 months of zoledronic acid treatment (dose escalation up to 0.05 mg/kg 6 monthly), his L2-4 and total body less head (TBLH) BMD increased by 13% and 7% respectively; Z-scores changed from −2.8 to −2.7 and from −1.7 to −1.5. Patient 2, a 10-year-old female with a maternally inherited c.3214C>T nonsense variant, developed acute back pain after a forward fall and showed wedging of T11 and L1. After 20 months of zoledronic acid (same dosing), L2-4 and TBLH BMD increased by 14% and 11%, while Z-scores shifted from −1.4 to −1.5 and from −2.1 to −2.0. Both patients had normal bone biochemistry. The authors note that SETD5 is a histone methyltransferase and suggest a possible role in osteogenic differentiation, but state that future systematic phenotyping is required to confirm the association.
The remaining abstracts cover other genetic intellectual disability syndromes. One 2019 series of 17 males with BRWD3 null variants reports moderate ID in 65% and mild in 35%, with mean head circumference +2.8 SD and mean BMI +2.0 SD. A 2022 cohort of eight individuals with de novo TAF4 loss-of-function variants proposes TAF4 as a novel dominant neurodevelopmental disease gene. A 2023 paper on DYRK1A-related ID describes four new patients and notes that ethnic differences in facial appearance can make the syndrome less recognisable. A 2010 study on KANSL1 haploinsufficiency states that chromosome deletions are more common than mutations, and that ID appears milder than expected in many cases, with key features including speech delay, distinctive facial dysmorphism, macrocephaly and friendly behaviour. Two 2018 papers on genotype-phenotype correlations in ID report that complex facial dysmorphia is common in ID with comorbid autism, while neurodegenerative-like features are overrepresented in ID with epilepsy.
What is missing for SETD5 haploinsufficiency is any systematic clinical or radiological phenotyping of bone health in a larger cohort, any preclinical model testing of drugs that might modify SETD5 function, and any trial design that could test whether bisphosphonates or other bone-targeted agents alter the natural history of the condition. The association with bone fragility rests on two cases, and no controlled data exist.
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 C Seminars in Medical Genetics · 2019 · 10 citations · open access
Null variants and deletions in <i>BRWD3</i> cause an X‐linked syndrome of mild–moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients
AbstractBRWD3 has been described as a cause of X-linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and 2 partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (<30%) of patients included cryptorchidism, neonatal hypotonia, and small joint hypermobility. This study delineates the clinical features associated with BRWD3 null variants and partial gene deletions, and suggests that BRWD3 should be included in the differential diagnosis of patients with an overgrowth-intellectual disability (OGID) phenotype, particularly in male patients with a mild or moderate intellectual disability associated with macrocephaly and/or obesity.
https://doi.org/10.1002/ajmg.c.31750Human Mutation · 2022 · 8 citations · open access
De novo putative loss‐of‐function variants in <i>TAF4</i> are associated with a neuro‐developmental disorder
AbstractTATA-binding protein associated factor 4 (TAF4) is a subunit of the Transcription Factor IID (TFIID) complex, a central player in transcription initiation. Other members of this multimeric complex have been implicated previously as monogenic disease genes in human developmental disorders. TAF4 has not been described to date as a monogenic disease gene. We here present a cohort of eight individuals, each carrying de novo putative loss-of-function (pLoF) variants in TAF4 and expressing phenotypes consistent with a neuro-developmental disorder (NDD). Common features include intellectual disability, abnormal behavior, and facial dysmorphisms. We propose TAF4 as a novel dominant disease gene for NDD, and coin this novel disorder "TAF4-related NDD" (T4NDD). We place T4NDD in the context of other disorders related to TFIID subunits, revealing shared features of T4NDD with other TAF-opathies.
https://doi.org/10.1002/humu.24444Clinical Genetics · 2021 · 7 citations · open access
Expanding the phenotype of <scp> <i>SETD5</i> </scp> ‐related disorder and presenting a novel association with bone fragility
AbstractPatients with SETD5-related disorder have variable features of intellectual disability (ID), facial dysmorphism, cardiac and skeletal abnormalities, behavioural problems, and short stature.1 We present two patients with pathogenic SETD5 variants and bone fragility, a new associated phenotype. Both patients were recruited via the deciphering developmental disorders (DDD) study (https://www.deciphergenomics.org/) and informed consent for publication was obtained. Patient 1: 14-year-old male (see Figure 1) with a pathogenic heterozygous c.1381_1388del, (p.Asn461fs) variant in exon 12 of SETD5.2 At 13 years of age, he was found to have multiple thoracic vertebral crush fractures following a minor fall from a swing at a low height onto his buttocks with resulting back pain which was investigated 10 days later. Radiographs showed multiple wedging of his thoracic spine both new and old which was confirmed on MRI-spine imaging. A transiliac bone biopsy showed mild osteopenia with increased cortical resorption and formation. Treatment with zoledronic acid (dose escalation over 9 months up to 0.05 mg/kg 6 monthly) resulted in improvement in DXA-measured bone parameters after 10 months: L2-4 and total body less head (TBLH) BMD increased by 13% and 7%, respectively; corresponding Z-scores increased from −2.8 to −2.7 and from −1.7 to −1.5, respectively. Patient 2: 10-year-old female (see Figure 1) in whom there were concerns with feeding difficulties, global developmental delay and poor weight gain in the first year of life. Her mother has mild–moderate ID with no bone fragility. She was found to carry a maternally inherited pathogenic nonsense variant in SETD5 c.3214C > T (p.Arg1072*). At 8 years of age, the patient developed acute lower back pain following a forward fall onto laminate kitchen flooring. Spinal radiographs identified wedging of T11 and L1 (10%–24%) and mild wedging of multiple other thoracic vertebrae (<10% anterior height loss). Treatment with zoledronic acid (dose escalation over 10 months up to 0.05 mg/kg 6 monthly) resulted in improvements in vertebral shapes, and in DXA-measured bone parameters after 20 months: L2-4 and TBLH MD increased by 14% and 11%, respectively; although corresponding Z-scores changed a little, from −1.4 to −1.5 and from −2.1 to −2.0, respectively. Bone-related biochemistry in both patients was normal (serum calcium, phosphate, alkaline phosphatase and 25-hydroxyvitamin D concentrations). There was no significant history of medication use impacting bone health or evidence of a connective tissue disorder in either patient. Patients reported here have features in keeping with a SETD5-related disorder. The key feature that has not previously been highlighted is bone fragility in the absence of a relevant family history of fractures. This suggests previously unrecognised, phenotypic association with SETD5-related disorder especially in the context of trio exome sequencing which has not identified any other cause for bone fragility. SETD5 is a ubiquitously expressed, highly conserved histone methyltransferase.3 There is evidence highlighting the important role of histone methyltransferase activity in osteogenic differentiation of mesenchymal stem cells (MSC).4 SET-domain containing histone lysine methyltransferases have been shown to contribute to the balance between osteogenesis and adipogenesis in MSCs and mice with loss of Setd2 causes a propensity for adipogenesis and loss of osteoblasts, thus raising the possibility of other SET-domain containing histone methyltransferases also having an impact on bone density.5 Compression fractures of spine can occur as a result of trauma, osteoporosis and heritable bone fragility conditions such as Osteogenesis Imperfecta (OI). Back pain and kyphosis can be initial presenting features although it may remain a late diagnosis. SETD5-related disorder remains a rare genetic condition; future systematic clinical and radiological phenotyping of these patients will be required to confirm this association. This paper highlights a need for a low threshold for bone health assessment in SETD5. Clinical screening and judicious use of imaging (e.g., lateral spine imaging with DXA) may enable early identification of bone fragility and ensure timely initiation of bone-targeted medication. The authors acknowledge the DDD study and both families for consenting to this publication. The authors declare no potential conflict of interest. The peer review history for this article is available at https://publons.com/publon/10.1111/cge.14014. Data sharing not applicable to this article as no data sets were generated or analysed during the current study
https://doi.org/10.1111/cge.14014Journal of Translational Genetics and Genomics · 2020 · 3 citations · open access
DeepGestalt analysis of the SETD5-associated intellectual disability syndrome
AbstractAim: This is the first computer-assisted study focused on the craniofacial features of the intellectual disability (ID)/developmental delay (DD) syndrome related to haploinsufficiency of the SETD5 gene (SET domain-containing protein 5, MIM#615743), which is a chromatin regulator. The purpose of this novel research is to better delineate the facial phenotype of this condition and identify the associated dysmorphic features to consider for clinical diagnosis.
https://doi.org/10.20517/jtgg.2020.05American Journal of Medical Genetics Part A · 2023 · 1 citations
Rock around <i>DYRK1A</i>: Ethnic diversity, clinical challenges
AbstractDYRK1A-related intellectual disability is a recently described syndrome characterized by microcephaly, global developmental delay, impaired speech development, and distinctive facial features, which let to define it as a recognizable syndrome. Here we report four new patients of different ethnicity, broadening the clinical phenotype of the condition and highlighting how ethnic influences in the facial appearance could make it less recognizable.
https://doi.org/10.1002/ajmg.a.63140Journal of Medical Genetics · 2010 · 0 citations · open access
Estudo teórico-experimental da influência do teor de umidade no fenômeno de spalling explosivo em concretos expostos a elevadas temperaturas
AbstractIn KANSL1 haploinsufficiency syndrome, chromosome deletions are greatly prevalent compared with KANSL1 mutations. The latter are sufficient in causing the full clinical phenotype. The degree of intellectual disability (ID) appears to be milder than expected in a considerable number of subjects with either chromosome deletion or KANSL1 mutation. Striking clinical criteria for enrolling patients into KANSL1 analysis include speech delay, distinctive facial dysmorphism, macrocephaly and friendly behaviour.
https://doi.org/10.1136/jmedgenet-2015-103184Figshare · 2018 · 0 citations · open access
Table_3_Widespread Genotype-Phenotype Correlations in Intellectual Disability.XLSX
Abstract<p>Background: Linking genotype to phenotype is a major aim of genetics research, yet the underlying biochemical mechanisms of many complex conditions continue to remain elusive. Recent research provides evidence that relevant gene-phenotype associations are discoverable in the study of intellectual disability (ID). Here we expand on that work, identifying distinctive gene interaction modules with unique enrichment patterns reflective of associated clinical features in ID.</p><p>Methods: Two hundred twelve forms of monogenic ID were curated according to comorbidities with autism and epilepsy. These groups were further subdivided according to secondary clinical manifestations of complex vs. simple facial dysmorphia and neurodegenerative-like features due to their clinical prominence, modest symptom overlap, and probable etiological divergence. An aggregate gene interaction ID network for these phenotype subgroups was discovered via a public database of known gene interactions: protein-protein, genetic, and mRNA coexpression. Additional annotation resources (Gene Ontology, Human Phenotype Ontology, TRANSFAC/JASPAR, and KEGG/WikiPathways) were utilized to assess functional and phenotypic enrichment patterns within subgroups.</p><p>Results: Phenotypic analysis revealed high rates of complex facial dysmorphia in ID with comorbid autism. In contrast, neurodegenerative-like features were overrepresented in ID with epilepsy. Network analysis subsequently showed that gene groups divided according to clinical features of interest resulted in distinctive interaction clusters, with unique functional enrichments according to gene set.</p><p>Conclusions: These data suggest that specific comorbid and secondary clinical features in ID are predictive of underlying genotype. In summary, ID form unique clusters, which are comprised of individual conditions with remarkable genotypic and phenotypic overlap.</p>
https://doi.org/10.3389/fpsyt.2018.00535.s005Figshare · 2018 · 0 citations · open access
Image_1_Widespread Genotype-Phenotype Correlations in Intellectual Disability.tif
Abstract<p>Background: Linking genotype to phenotype is a major aim of genetics research, yet the underlying biochemical mechanisms of many complex conditions continue to remain elusive. Recent research provides evidence that relevant gene-phenotype associations are discoverable in the study of intellectual disability (ID). Here we expand on that work, identifying distinctive gene interaction modules with unique enrichment patterns reflective of associated clinical features in ID.</p><p>Methods: Two hundred twelve forms of monogenic ID were curated according to comorbidities with autism and epilepsy. These groups were further subdivided according to secondary clinical manifestations of complex vs. simple facial dysmorphia and neurodegenerative-like features due to their clinical prominence, modest symptom overlap, and probable etiological divergence. An aggregate gene interaction ID network for these phenotype subgroups was discovered via a public database of known gene interactions: protein-protein, genetic, and mRNA coexpression. Additional annotation resources (Gene Ontology, Human Phenotype Ontology, TRANSFAC/JASPAR, and KEGG/WikiPathways) were utilized to assess functional and phenotypic enrichment patterns within subgroups.</p><p>Results: Phenotypic analysis revealed high rates of complex facial dysmorphia in ID with comorbid autism. In contrast, neurodegenerative-like features were overrepresented in ID with epilepsy. Network analysis subsequently showed that gene groups divided according to clinical features of interest resulted in distinctive interaction clusters, with unique functional enrichments according to gene set.</p><p>Conclusions: These data suggest that specific comorbid and secondary clinical features in ID are predictive of underlying genotype. In summary, ID form unique clusters, which are comprised of individual conditions with remarkable genotypic and phenotypic overlap.</p>
https://doi.org/10.3389/fpsyt.2018.00535.s001Disease 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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