RARE DISEASE
Rubinstein-Taybi syndrome due to CREBBP mutations
Rubinstein-Taybi syndrome due to CREBBP mutations
Rubinstein-Taybi syndrome due to CREBBP mutations
Drug discovery
0
drugs
With orphan designations
Overview
Rubinstein-Taybi syndrome (RSTS) due to CREBBP mutations is a rare autosomal dominant disorder characterized by distinctive facial features (downslanting palpebral fissures, beaked nose), intellectual disability, broad thumbs/halluces, and growth retardation. Over 90% of patients survive to adulthood but require multidisciplinary care for complications including cardiac defects, recurrent infections, and behavioral issues [1][3][12]. Diagnosis relies on clinical evaluation confirmed by CREBBP genetic testing, with mutations identified in ~55% of cases [10][16]. No cure exists; management focuses on symptomatic support and surveillance [17].
Burden
High morbidity: 83% develop behavioral/psychiatric disorders (ADHD, OCD, aggression), 73% experience chronic gastrointestinal issues (constipation, reflux) [3][10]
Lifelong care requirements: 50% require adult surgeries, 62% have chronic sleep disturbances, and 65% develop keloids/adnexal skin disorders [3][18]
Socioeconomic impact: intensive caregiver support, reduced quality of life, and elevated healthcare costs due to multisystem complications [3][10]
Therapies
Multidisciplinary care: early developmental interventions (physical/occupational therapy, speech therapy), behavioral therapies, and surgical correction of skeletal/cardiac anomalies [2][6][10]
Routine surveillance: annual evaluations for vision, hearing, cardiac/renal function, and malignancy screening [10][17]
Investigational approaches: HDAC inhibitors (e.g., vorinostat) targeting epigenetic dysregulation in preclinical models [16]
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare neoplastic diseases, rare neurological diseases, rare ophthalmic disorders, rare renal diseases, rare transplant-related disorders
Research Papers
24 drug discovery papers about Rubinstein-Taybi syndrome due to CREBBP mutations, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
24 drug discovery papers about Rubinstein-Taybi syndrome due to CREBBP mutations, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-11 | Mutations in KAT3 family of lysine acetyl transferases impair neural crest migration in Rubinstein Taybi syndrome models.
Rubinstein Taybi syndrome (RSTS), a rare congenital disease, is caused by mutations in lysine acetyl transferase type 3 (KAT3) genes, EP300 and CREBBP. Many of the tissues affected in RSTS are derived from the neural crest (NC). Hence, we proposed that NC development would be perturbed in RSTS. Zebrafish RSTS models generated by knocking down or mutating ep300a and crebbpa genes reveal defects in NC migration. This effect on migration is conserved in NC cells generated from human RSTS patient-derived induced pluripotent stem cells (iPSC) cells. The defects in NC migration can be partially reversed by HDAC inhibition in morphant embryos. KAT3 knockdown causes downregulation of snai1b and snai2 and upregulation of cdh6, important regulators of epithelial to mesenchymal transition (EMT). Snai2 is known to repress CDH6, also known as cadherin 6b, in chick NC cells facilitating their delamination from the neural tube and migration. We demonstrate for the first time that NC migration is defective in zebrafish and iPSC models of RSTS. We make a case for classifying RSTS as a neurocristopathy. We propose that KAT3 genes control NC migration through regulation of EMT genes snai2 and snai1b.
2025-10-08 | Genomic Sequencing Insights Into a Rare Case of High-Risk Diffuse Large B-cell Lymphoma (DLBCL) Associated With Rubinstein-Taybi Syndrome.
We report a rare case of a Rubinstein-Taybi syndrome (RSTS) patient who developed diffuse large B-cell lymphoma (DLBCL). RSTS is a very rare, genetic, developmental disease. RSTS patients have been reported to have some predilection for certain cancers. The patient had both germline and somatic mutations in the CREBBP (cyclic-AMP-regulated enhancer-binding protein) gene. CREBBP has been reported to be associated with poor prognosis and less response to chemotherapy. We treated the patient with Rituxan with EPOCH (R-EPOCH) with excellent response. Based on the rarity of this diagnosis and the development of lymphoma in this patient, we sought to establish a genomic connection between RSTS and its association with high-risk DLBCL. The distinct response observed in this case warrants further investigation into the potential benefits of intensified therapies in DLBCL patients harboring specific genetic alterations such as CREBBP.
2024-02-20 | Unraveling the Mechanism of Response: Genomic Sequencing Insights into a Rare Case of Rubinstein-Taybi Syndrome-Associated High-Risk Diffuse Large B-Cell Lymphoma
Abstract Background Rubinstein-Taybi syndrome (RSTS) is a very rare, genetic, developmental disease. RSTS patients have been reported to have some predilection to certain cancers. We report a rare case of Rubinstein-Taybi syndrome patient that developed Diffuse large B cell lymphoma (DLBCL). Case Presentation Patient had both germline and somatic mutation in CREBBP (the cyclic-AMP-regulated enhancer-binding protein) gene. CREBBP has been reported to be associated with poor prognosis and less response to chemotherapy. We treated the patient with R-EPOCH with excellent response. Based on the rarity of this diagnosis and development of lymphoma in this patient, we sought to establish a genomic connection between Rubinstein-Taybi Syndrome and its association with high-risk DLBCL. The distinct response observed in this case warrants further investigation into the potential benefits of intensified therapies in diffuse large B-cell lymphoma patients harboring specific genetic alterations like CREBBP as seen in this case. Conclusions This case report gives Genomic Sequencing Insights into a Rare Case of Rubinstein-Taybi Syndrome-associated high-risk Diffuse Large B-Cell Lymphoma.
2023-07-07 | EP300 facilitates human trophoblast stem cell differentiation.
Early placenta development involves cytotrophoblast differentiation into extravillous trophoblast (EVT) and syncytiotrophoblast (STB). Defective trophoblast development and function may result in severe pregnancy complications, including fetal growth restriction and pre-eclampsia. The incidence of these complications is increased in pregnancies of fetuses affected by Rubinstein-Taybi syndrome, a developmental disorder predominantly caused by heterozygous mutations in CREB-binding protein (CREBBP) or E1A-binding protein p300 (EP300). Although the acetyltransferases CREBBP and EP300 are paralogs with many overlapping functions, the increased incidence of pregnancy complications is specific for EP300 mutations. We hypothesized that these complications have their origin in early placentation and that EP300 is involved in that process. Therefore, we investigated the role of EP300 and CREBBP in trophoblast differentiation, using human trophoblast stem cells (TSCs) and trophoblast organoids. We found that pharmacological CREBBP/EP300 inhibition blocks differentiation of TSCs into both EVT and STB lineages, and results in an expansion of TSC-like cells under differentiation-inducing conditions. Specific targeting by RNA interference or CRISPR/Cas9-mediated mutagenesis demonstrated that knockdown of EP300 but not CREBBP, inhibits trophoblast differentiation, consistent with the complications seen in Rubinstein-Taybi syndrome pregnancies. By transcriptome sequencing, we identified transforming growth factor alpha (TGFA, encoding TGF-α) as being strongly upregulated upon EP300 knockdown. Moreover, supplementing differentiation medium with TGF-α, which is a ligand for the epidermal growth factor receptor (EGFR), likewise affected trophoblast differentiation and resulted in increased TSC-like cell proliferation. These findings suggest that EP300 facilitates trophoblast differentiation by interfering with at least EGFR signaling, pointing towards a crucial role for EP300 in early human placentation.
2021-06-21 | Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients.
Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder caused by mutations in CREBBP or EP300 genes encoding CBP/p300 lysine acetyltransferases. We investigated the efficacy of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) in ameliorating morphological abnormalities of iPSC-derived young neurons from P149 and P34 CREBBP-mutated patients and hypoexcitability of mature neurons from P149. Neural progenitors from both patients' iPSC lines were cultured one week with TSA 20 nM and, only P149, for 6 weeks with TSA 0.2 nM, in parallel to neural progenitors from controls. Immunofluorescence of MAP2/TUJ1 positive cells using the Skeletonize Image J plugin evidenced that TSA partially rescued reduced nuclear area, and decreased branch length and abnormal end points number of both 45 days patients' neurons, but did not influence the diminished percentage of their neurons with respect to controls. Patch clamp recordings of TSA-treated post-mitotic P149 neurons showed complete/partial rescue of sodium/potassium currents and significant enhancement of neuron excitability compared to untreated replicas. Correction of abnormalities of P149 young neurons was also affected by valproic acid 1 mM for 72 h, with some variation, with respect to TSA, on the morphological parameter. These findings hold promise for development of an epigenetic therapy to attenuate RSTS patients cognitive impairment.
small molecules
2026-05-11 | Mutations in KAT3 family of lysine acetyl transferases impair neural crest migration in Rubinstein Taybi syndrome models.
Rubinstein Taybi syndrome (RSTS), a rare congenital disease, is caused by mutations in lysine acetyl transferase type 3 (KAT3) genes, EP300 and CREBBP. Many of the tissues affected in RSTS are derived from the neural crest (NC). Hence, we proposed that NC development would be perturbed in RSTS. Zebrafish RSTS models generated by knocking down or mutating ep300a and crebbpa genes reveal defects in NC migration. This effect on migration is conserved in NC cells generated from human RSTS patient-derived induced pluripotent stem cells (iPSC) cells. The defects in NC migration can be partially reversed by HDAC inhibition in morphant embryos. KAT3 knockdown causes downregulation of snai1b and snai2 and upregulation of cdh6, important regulators of epithelial to mesenchymal transition (EMT). Snai2 is known to repress CDH6, also known as cadherin 6b, in chick NC cells facilitating their delamination from the neural tube and migration. We demonstrate for the first time that NC migration is defective in zebrafish and iPSC models of RSTS. We make a case for classifying RSTS as a neurocristopathy. We propose that KAT3 genes control NC migration through regulation of EMT genes snai2 and snai1b.
2025-10-08 | Genomic Sequencing Insights Into a Rare Case of High-Risk Diffuse Large B-cell Lymphoma (DLBCL) Associated With Rubinstein-Taybi Syndrome.
We report a rare case of a Rubinstein-Taybi syndrome (RSTS) patient who developed diffuse large B-cell lymphoma (DLBCL). RSTS is a very rare, genetic, developmental disease. RSTS patients have been reported to have some predilection for certain cancers. The patient had both germline and somatic mutations in the CREBBP (cyclic-AMP-regulated enhancer-binding protein) gene. CREBBP has been reported to be associated with poor prognosis and less response to chemotherapy. We treated the patient with Rituxan with EPOCH (R-EPOCH) with excellent response. Based on the rarity of this diagnosis and the development of lymphoma in this patient, we sought to establish a genomic connection between RSTS and its association with high-risk DLBCL. The distinct response observed in this case warrants further investigation into the potential benefits of intensified therapies in DLBCL patients harboring specific genetic alterations such as CREBBP.
2024-02-20 | Unraveling the Mechanism of Response: Genomic Sequencing Insights into a Rare Case of Rubinstein-Taybi Syndrome-Associated High-Risk Diffuse Large B-Cell Lymphoma
Abstract Background Rubinstein-Taybi syndrome (RSTS) is a very rare, genetic, developmental disease. RSTS patients have been reported to have some predilection to certain cancers. We report a rare case of Rubinstein-Taybi syndrome patient that developed Diffuse large B cell lymphoma (DLBCL). Case Presentation Patient had both germline and somatic mutation in CREBBP (the cyclic-AMP-regulated enhancer-binding protein) gene. CREBBP has been reported to be associated with poor prognosis and less response to chemotherapy. We treated the patient with R-EPOCH with excellent response. Based on the rarity of this diagnosis and development of lymphoma in this patient, we sought to establish a genomic connection between Rubinstein-Taybi Syndrome and its association with high-risk DLBCL. The distinct response observed in this case warrants further investigation into the potential benefits of intensified therapies in diffuse large B-cell lymphoma patients harboring specific genetic alterations like CREBBP as seen in this case. Conclusions This case report gives Genomic Sequencing Insights into a Rare Case of Rubinstein-Taybi Syndrome-associated high-risk Diffuse Large B-Cell Lymphoma.
2023-07-07 | EP300 facilitates human trophoblast stem cell differentiation.
Early placenta development involves cytotrophoblast differentiation into extravillous trophoblast (EVT) and syncytiotrophoblast (STB). Defective trophoblast development and function may result in severe pregnancy complications, including fetal growth restriction and pre-eclampsia. The incidence of these complications is increased in pregnancies of fetuses affected by Rubinstein-Taybi syndrome, a developmental disorder predominantly caused by heterozygous mutations in CREB-binding protein (CREBBP) or E1A-binding protein p300 (EP300). Although the acetyltransferases CREBBP and EP300 are paralogs with many overlapping functions, the increased incidence of pregnancy complications is specific for EP300 mutations. We hypothesized that these complications have their origin in early placentation and that EP300 is involved in that process. Therefore, we investigated the role of EP300 and CREBBP in trophoblast differentiation, using human trophoblast stem cells (TSCs) and trophoblast organoids. We found that pharmacological CREBBP/EP300 inhibition blocks differentiation of TSCs into both EVT and STB lineages, and results in an expansion of TSC-like cells under differentiation-inducing conditions. Specific targeting by RNA interference or CRISPR/Cas9-mediated mutagenesis demonstrated that knockdown of EP300 but not CREBBP, inhibits trophoblast differentiation, consistent with the complications seen in Rubinstein-Taybi syndrome pregnancies. By transcriptome sequencing, we identified transforming growth factor alpha (TGFA, encoding TGF-α) as being strongly upregulated upon EP300 knockdown. Moreover, supplementing differentiation medium with TGF-α, which is a ligand for the epidermal growth factor receptor (EGFR), likewise affected trophoblast differentiation and resulted in increased TSC-like cell proliferation. These findings suggest that EP300 facilitates trophoblast differentiation by interfering with at least EGFR signaling, pointing towards a crucial role for EP300 in early human placentation.
2021-06-21 | Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients.
Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder caused by mutations in CREBBP or EP300 genes encoding CBP/p300 lysine acetyltransferases. We investigated the efficacy of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) in ameliorating morphological abnormalities of iPSC-derived young neurons from P149 and P34 CREBBP-mutated patients and hypoexcitability of mature neurons from P149. Neural progenitors from both patients' iPSC lines were cultured one week with TSA 20 nM and, only P149, for 6 weeks with TSA 0.2 nM, in parallel to neural progenitors from controls. Immunofluorescence of MAP2/TUJ1 positive cells using the Skeletonize Image J plugin evidenced that TSA partially rescued reduced nuclear area, and decreased branch length and abnormal end points number of both 45 days patients' neurons, but did not influence the diminished percentage of their neurons with respect to controls. Patch clamp recordings of TSA-treated post-mitotic P149 neurons showed complete/partial rescue of sodium/potassium currents and significant enhancement of neuron excitability compared to untreated replicas. Correction of abnormalities of P149 young neurons was also affected by valproic acid 1 mM for 72 h, with some variation, with respect to TSA, on the morphological parameter. These findings hold promise for development of an epigenetic therapy to attenuate RSTS patients cognitive impairment.
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