Rubinstein Taybi Research Articles

Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations.

Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc.

RUBINSTEIN TAYBI SYNDROME

Rubinstein Taybi Syndrome (RTS) was first described in 1963 by Rubinsteinand Taybi. The characteristic features of this syndrome include broad thumbs and toes,facial abnormalities like hypertelorism, beaked nose, micrognathia, microcephaly and mentalretardation. Cardiac, renal, ophthalmological and various orthopedic problems can also occur.Prevalence in the general population is approximately 1 case per 300,000 persons and is as highas 1 case per 10,000 live births. There is no definite inheritance pattern so far and recurrenceis very unlikely. In some patients, multiple chromosomal anomalies have been described. Wereport here a case of Rubinstein Taybi syndrome in an 18 months old girl presented with typicalfeatures which is the first case reported in our population.

English

Rubinstein Taybi Syndrome (RTS) was first described in 1963 by Rubinsteinand Taybi. The characteristic features of this syndrome include broad thumbs and toes,facial abnormalities like hypertelorism, beaked nose, micrognathia, microcephaly and mentalretardation. Cardiac, renal, ophthalmological and various orthopedic problems can also occur.Prevalence in the general population is approximately 1 case per 300,000 persons and is as highas 1 case per 10,000 live births. There is no definite inheritance pattern so far and recurrenceis very unlikely. In some patients, multiple chromosomal anomalies have been described. Wereport here a case of Rubinstein Taybi syndrome in an 18 months old girl presented with typicalfeatures which is the first case reported in our population.

Syndromes with supernumerary teeth.

While most supernumerary teeth are idiopathic, they can be associated with a number of Mendelian syndromes. However, this can also be a coincidental finding, since supernumerary teeth occur in 6% or more of the normal population. To better define this relationship, we analyzed the evidence for specific associations. We excluded conditions with a single affected patient reported, supernumerary teeth adjacent to clefts or other forms of alveolar disruption (as secondary rather than primary findings), and natal teeth, which can involve premature eruption of a normal tooth. Since, the cause of supernumerary teeth shows considerable heterogeneity, certain findings are less likely to be coincidental, such as five or more supernumerary teeth in a single patient, or locations outside of the premaxilla. We found only eight genetic syndromes with strong evidence for an association: cleidocranial dysplasia; familial adenomatous polyposis; trichorhinophalangeal syndrome, type I; Rubinstein-Taybi syndrome; Nance-Horan syndrome; Opitz BBB/G syndrome; oculofaciocardiodental syndrome; and autosomal dominant Robinow syndrome. There is also suggestive evidence of an association with two uncommon disorders, Kreiborg-Pakistani syndrome (craniosynostosis and dental anomalies), and insulin-resistant diabetes mellitus with acanthosisnigricans. An association of a Mendelian disorder with a low frequency manifestation of supernumerary teeth is difficult to exclude without large numbers, but several commonly cited syndromes lacked evidence for clear association, including Hallermann-Streiff syndrome, Fabry disease, Ehlers-Danlos syndrome, Apert and Crouzon syndromes, Zimmermann-Laband syndrome, and Ellis-van Creveld syndrome. © 2016 Wiley Periodicals, Inc.

Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein–Taybi and Filippi syndromes

Rubinstein-Taybi syndrome (RTS, OMIM 180849) and Filippi syndrome (FLPIS, OMIM 272440) are both rare syndromes, with multiple congenital anomalies and intellectual deficit (MCA/ID). We present a patient with intellectual deficit, short stature, bilateral syndactyly of hands and feet, broad thumbs, ocular abnormalities, and dysmorphic facial features. These clinical features suggest both RTS and FLPIS. Initial DNA analysis of DNA isolated from blood did not identify variants to confirm either of these syndrome diagnoses. Whole-exome sequencing identified a homozygous variant in C9orf173, which was novel at the time of analysis. Further Sanger sequencing analysis of FLPIS cases tested negative for CKAP2L variants did not, however, reveal any further variants. Subsequent analysis using DNA isolated from buccal mucosa revealed a mosaic variant in CREBBP. This report highlights the importance of excluding mosaic variants in patients with a strong but atypical clinical presentation of a MCA/ID syndrome if no disease-causing variants can be detected in DNA isolated from blood samples. As the striking syndactyly observed in the present case is typical for FLPIS, we suggest CREBBP analysis in saliva samples for FLPIS syndrome cases in which no causal CKAP2L variant is detected.

Holoprosencephaly and Recurrent Episodes of Severe Neurogenic Hypernatremia

Holoprosencephaly (HPE) is a severe and complex malformation caused by incomplete cleavage of the prosencephalon and incomplete development of paramedian structures. Many causes have been recognized as responsible for this malformation including maternal diabetes, chromosomal abnormalities, and heterozygous mutations, involving four major genes ( SHH , Z1C2 , SIX3 , and TGIF ) and other less frequently reported genes. HPE has frequently been reported as a feature of complex malformative syndromes such as Smith–Lemli–Opitz syndrome, CHARGE syndrome (acronym of Coloboma, Heart defects, choanal Atresia, Retardation of growth and/or development, Genitourinary malformation and Ear abnormalities), and Rubinstein–Taybi syndrome. Moreover, children with HPE may present with other anomalies aside from those of the brain and face, including endocrine disorders such as diabetes insipidus, adrenal hypoplasia, hypogonadism, thyroid hypoplasia, and growth hormone deficiency. We report a boy with typical clinical signs of HPE including neuroradiologic findings resembling severe congenital hydrocephalus. The patient also presented with a specific metabolic anomaly consisting of recurrent episodes of hypernatremia.

Maternally inherited autosomal dominant intellectual disability caused by 16p13.3 microduplication

A 16p13.3 duplication syndrome has been recently suggested to be a novel recognizable syndrome as a reciprocal microduplication disease of Rubinstein–Taybi syndrome. The CREBBP gene is believed to be the dosage-sensitive critical gene responsible for the reciprocal duplication and deletion syndrome. Descriptions so far have been de novo. Here, we report a very rare case of a maternally inherited a −1 Mb sized duplication on 16p13.3 identified by SNP array testing. The patient showed moderate intellectual disability, normal growth, and characteristic facial features. The patient's mother also had mild intellectual disability, normal growth, camptodactyly, proximally implanted small thumbs, and distinctive facial features. The study provides additional information that furthers the understanding and delineation of 16p13.3 duplication syndrome.

Electroclinical phenotype in Rubinstein–Taybi syndrome

ObjectiveRubinstein–Taybi syndrome (RSTS) is a rare congenital disorder (1:125.000) characterized by growth retardation, psychomotor developmental delay, microcephaly and dysmorphic features. In 25% of patients seizures have been described, and in about 66% a wide range of EEG abnormalities, but studies on neurological features are scant and dated.The aim of this study is to describe the electroclinical phenotype of twenty-three patients with RSTS, and to try to correlate electroclinical features with neuroradiological, cognitive and genetic features. Patients and methodsElectroclinical features of twenty-three patients with RSTS (age between18months and 20years) were analyzed. Sleep and awake EEG was performed in twenty-one patients, and brain MRI in nineteen patients. All subjects received cognitive evaluation. ResultsEEG abnormalities were observed in 76% (16/21) of patients. A peculiar pattern prevalent in sleep, characterized by slow monomorphic activity on posterior regions was also observed in 33% (7/21) of patients. Almost no patient presented seizures. Eighty-four percentage of patients had brain MRI abnormalities, involving corpus callosum and/or posterior periventricular white matter. Average General Quotient (GQ) was 52, while average IQ was 55, corresponding to mild Intellectual Disability. The homogeneous electroclinical pattern was observed mainly in patients with more severe neuroradiologic findings and moderate Intellectual Disability/Developmental Disability (ID/DD). No genotype-phenotype correlations were found. ConclusionThe specific electroclinical and neuroradiological features described may be part of a characteristic RSTS phenotype. Wider and longitudinal studies are needed to verify its significance and impact on diagnosis, prognosis and clinical management of RSTS patients.

Ultra-Rare Syndromes: The Example of Rubinstein-Taybi Syndrome.

Rubinstein-Taybi syndrome (RSTS) is a rare, congenital, plurimalformative, and neurodevelopmental disorder. Clinical diagnosis can be complicated by the heterogeneous clinical presentation and the lack of a consensus list of diagnostic criteria, and it is confirmed by molecular tests in approximately 55 to 78% of cases. The etiology is partially known with mutations in two functionally related genes: CREBBP and EP300. Notwithstanding the knowledge on clinical, genetic, and allelic heterogeneity, no clear genotype-phenotype correlation has yet been established. Standardized guidelines for the management of pediatric patients are available and therapy for RSTS patients is currently only symptomatic. In this article, several clinic and genetic aspects of RSTS are critically reviewed.

The role of epigenomics in the neurodegeneration of ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is a multisystem disease characterized by neurodegeneration in the CNS [1–5]. The earliest and most profound neuropathology involves the Purkinje and granule cells of the cerebellum. A-T is caused by mutation of the A-T mutated (ATM) gene, which is ubiquitously expressed throughout development and encodes a serine/threonine protein kinase of the phosphatidylinositol-3 kinase-related kinase family [6]. A-T is classified as a rare neurodegenerative disease, mainly impacting on cerebellum integrity and functioning, resulting in a progressive deterioration of motor functional capabilities [5]. Moreover, since there is currently no effective treatment to cure or even slow down the rate of cerebellar neurodegeneration, A-T significantly decreases life quality of those suffering from it. The best-known function of ATM is to ensure the integrity of the genome. After DNA damage, ATM activates cell cycle checkpoints, arresting the cycle until DNA repair is complete [7]. Its role in maintaining the health and survival of neurons is complex. Consistent with its function in DNA damage repair [8], ATM protects postmitotic neurons from degeneration by suppressing the cell cycle [9–11]. While non-neurological phenotypes are also found, including immune system defects, germ cell defects, hypersensitivity to ionizing radiation and increased susceptibility to, it is the origins of the CNS motor phenotypes of A-T that are the most poorly understood. Yet the pathway that leads from these defects to neuronal cell loss and the other classical neurological phenotypes remains unknown. Epigenetic systems, heritable changes in gene expression that do not involve coding sequence modifications, include DNA methylation, histone modifications and chromatin remodeling, and noncoding RNA regulation. These types of changes have been proposed to be responsible for controlling the expression and function of genes and have emerged as important mediators of development and aging [12–19]. Several diseases are known to have a multifactorial origin, depending not only on genetic but also on environmental factors. They are called ‘complex disorders’ and include cardiovascular disease, cancer, diabetes, and neuropsychiatric and neurodegenerative diseases [20–26]. The neurological disorder most intensely studied with regard to epigenetic changes is Rett syndrome; patients with Rett syndrome have neurodevelopmental defects associated with mutations in MeCP2, which encodes the methyl CpG binding protein 2, that binds to methylated DNA. Other mental retardation disorders are also linked to the disruption of genes involved in epigenetic mechanisms; such disorders include α thalassaemia/mental retardation X-linked syndrome, Rubinstein–Taybi syndrome, and Coffin–Lowry syndrome [26]. Due to epigenetic variability among different neuronal cell types and epigenetic instability during development and maturation of neurons, whether specific epigenetic system is involved in the vulnerability of ATM-deficient Purkinje cell with a large and pale nuclei will be helpful to understand A-T neurodegeneration. In this review, we place emphasis both on addressing nuclear accumulation of histone The role of epigenomics in the neurodegeneration of ataxia-telangiectasia

Expanding the phenotypic spectrum in EP300-related Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RSTS) can be caused by heterozygous mutations or deletions involving CREBBP or, less commonly, EP300. To date, only 15 patients with EP300 mutations have been clinically described. Frequently reported manifestations in these patients include characteristic facial and limb features, varying degrees of neurocognitive dysfunction, and maternal preeclampsia. Other congenital anomalies are less frequently reported. We describe a child found to have a de novo EP300 mutation (c.4933C>T, predicted to result in p.Arg1645X) through research-based whole-genome sequencing of the family trio. The child's presentation involved dysmorphic features as well as unilateral renal agenesis, a myelomeningocele, and minor genitourinary anomalies. The involvement of congenital anomalies in all 16 clinically described patients with EP300 mutations (25% of which have been identified by "hypothesis free" methods, including microarray, exome, and whole-genome sequencing) is reviewed. In summary, genitourinary anomalies have been identified in 38%, cardiovascular anomalies in 25%, spinal/vertebral anomalies in 19%, other skeletal anomalies in 19%, brain anomalies in 13%, and renal anomalies in 6%. Our patient expands the phenotypic spectrum in EP300-related RSTS; this case demonstrates the evolving practice of clinical genomics related to increasing availability of genomic sequencing methods.

Fever of Unknown Origin with Psychiatric Complaints in a Patient with Rubinstein-Taybi Syndrome

Rubinstein–Taybi syndrome (RTS) is a rare genetic disorder characterized by mental retardation, postnatal growth deficiency, microcephaly, specific facial characteristics, broad thumbs, and big toes. Presence of dental problems and inadequate follow-up in RTS, as well as difficulty in self-care, poses a substantial health threat. This case report describes the evaluation of a 27-year-old female RTS patient diagnosed with fever of unknown origin (FUO) with psychiatric complaints and underlines the importance of physical examination including oral cavity in patients with difficulties in expressing their physical complaints.

High myopia, V-pattern esotropia and bilateral nasolacrimal duct obstruction in a child with Rubinstein–Taybi syndrome

We report a female child of Indian origin with Rubinstein–Taybi syndrome with ocular features of convergent strabismus (V-pattern esotropia), bilateral high myopia and congenital nasolacrimal duct obstruction. We present the details of the management of this case and the final outcome. This case report not only highlights the variability of the ocular features, but also the importance of an ocular examination in patients with Rubinstein–Taybi syndrome.

Clinical and mutational spectrum in Korean patients with Rubinstein-Taybi syndrome: the spectrum of brain MRI abnormalities.

Rubinstein-Taybi syndrome (RSTS) is one of the neurodevelopmental disorders caused by mutations of epigenetic genes. The CREBBP gene is the most common causative gene, encoding the CREB-binding protein with histone acetyltransferase (HAT) activity, an epigenetic modulator. To date, there have been few reports on the structural abnormalities of the brain in RSTS patients. In addition, there are no reports on the analysis of CREBBP mutations in Korean RSTS patients. We performed mutational analyses on 16 unrelated patients with RSTS, with diagnosis based on the typical clinical features. Their medical records and brain MRI images were reviewed retrospectively. Ten of 16 patients (62.5%) had mutations in the CREBBP gene. The mutations included five frameshift mutations (31.2%), two nonsense mutations (12.5%), and three multiexon deletions (18.8%). There were no remarkable significant differences in the clinical features between those with and without a CREBBP mutation, although brain MRI abnormalities were more frequently observed in those with a CREBBP mutation. Seven of 10 patients in whom brain imaging was performed had structural abnormalities, including Chiari malformation type 1, thinning of the corpus callosum, and delayed myelination. There were no differences in delayed development or cognitive impairment between those with and without abnormal brain images, while epilepsy was involved in two patients who had abnormalities on brain MRI images. We investigated the spectrum of CREBBP mutations in Korean patients with RSTS for the first time. Eight novel mutations extended the genetic spectrum of CREBBP mutations in RSTS patients. This is also the first study showing the prevalence and spectrum of abnormalities on brain MRI in RSTS patients.

Simulations suggest pharmacological methods for rescuing long-term potentiation

Congenital cognitive dysfunctions are frequently due to deficits in molecular pathways that underlie the induction or maintenance of synaptic plasticity. For example, Rubinstein–Taybi syndrome (RTS) is due to a mutation in cbp, encoding the histone acetyltransferase CREB-binding protein (CBP). CBP is a transcriptional co-activator for CREB, and induction of CREB-dependent transcription plays a key role in long-term memory (LTM). In animal models of RTS, mutations of cbp impair LTM and late-phase long-term potentiation (LTP). As a step toward exploring plausible intervention strategies to rescue the deficits in LTP, we extended our previous model of LTP induction to describe histone acetylation and simulated LTP impairment due to cbp mutation. Plausible drug effects were simulated by model parameter changes, and many increased LTP. However no parameter variation consistent with a effect of a known drug class fully restored LTP. Thus we examined paired parameter variations consistent with effects of known drugs. A pair that simulated the effects of a phosphodiesterase inhibitor (slowing cAMP degradation) concurrent with a deacetylase inhibitor (prolonging histone acetylation) restored normal LTP. Importantly these paired parameter changes did not alter basal synaptic weight. A pair that simulated the effects of a phosphodiesterase inhibitor and an acetyltransferase activator was similarly effective. For both pairs strong additive synergism was present. The effect of the combination was greater than the summed effect of the separate parameter changes. These results suggest that promoting histone acetylation while simultaneously slowing the degradation of cAMP may constitute a promising strategy for restoring deficits in LTP that may be associated with learning deficits in RTS. More generally these results illustrate how the strategy of combining modeling and empirical studies may provide insights into the design of effective therapies for improving long-term synaptic plasticity and learning associated with cognitive disorders.

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A patient with a de-novo deletion 3p25.3 and features overlapping with Rubinstein–Taybi syndrome

Czeschik, Johanna Christinaa; Albrecht, Beatea; Kayserili, Hülyab; Kuechler, Almaa; Wagner, Nicholasa; Wieczorek, Dagmara; Lüdecke, Hermann-Josefa Author Information

Multiple facets of CBP in forebrain interneuron development

Rubinstein–Taybi Syndrome (RTS), where the transcriptional co-activator and histone acetyltransferase CBP is mutated and haploinsufficient, is often associated with epilepsy, a disorder that is frequently due to perturbations in the generation of GABAergic interneurons and/or the inhibitory neurotransmitter GABA. Hereby, Tsui et al., recently published in Developmental Biology, asked whether CBP was necessary for the appropriate genesis and differentiation of interneurons in the murine forebrain. This paper defined multiple roles of CBP during forebrain interneuron development. In particular, CBP not only acts as a pro-differentiation factor to enhance the differentiation of ventral forebrain precursors to interneurons, but also modulates the maturation of interneurons by promoting acquisition of a GABAergic interneuron phenotype in the newborn neurons. Thus, deficits in interneuron development caused by CBP haploinsufficiency provide a potential explanation for the epilepsy seen in individuals with RTS.

Epigenetic Mechanisms of Rubinstein–Taybi Syndrome

Rubinstein-Taybi syndrome (RTS) is an incurable genetic disorder with combination of mental retardation and physical features including broad thumbs and toes, craniofacial abnormalities, and growth deficiency. While the autosomal dominant mode of transmission is limitedly known, the majority of cases are attributable to de novo mutations in RTS. The first identified gene associated with RTS is CREB-binding protein (CREBBP/CBP). Alterations of the epigenetic 'histone code' due to dysfunction of the CBP histone acetyltransferase activity deregulate gene transcriptions that are prominently linked to RTS pathogenesis. In this review, we discuss how CBP mutation contributes to modifications of histone and how histone deacetylase inhibitors are therapeutically applicable to epigenetic conditioning in RTS. Since most genetic mutations are irreversible and therapeutic approaches are limited, therapeutic targeting of reversible epigenetic components altered in RTS may be an ideal strategy. Expeditious further study on the role of the epigenetic mechanisms in RTS is encouraged to identify novel epigenetic markers and therapeutic targets to treat RTS.

CBP regulates the differentiation of interneurons from ventral forebrain neural precursors during murine development

The mechanisms that regulate appropriate genesis and differentiation of interneurons in the developing mammalian brain are of significant interest not only because interneurons play key roles in the establishment of neural circuitry, but also because when they are deficient, this can cause epilepsy. In this regard, one genetic syndrome that is associated with deficits in neural development and epilepsy is Rubinstein–Taybi Syndrome (RTS), where the transcriptional activator and histone acetyltransferase CBP is mutated and haploinsufficient. Here, we have asked whether CBP is necessary for the appropriate genesis and differentiation of interneurons in the murine forebrain, since this could provide an explanation for the epilepsy that is associated with RTS. We show that CBP is expressed in neural precursors within the embryonic medial ganglionic eminence (MGE), an area that generates the vast majority of interneurons for the cortex. Using primary cultures of MGE precursors, we show that knockdown of CBP causes deficits in differentiation of these precursors into interneurons and oligodendrocytes, and that overexpression of CBP is by itself sufficient to enhance interneuron genesis. Moreover, we show that levels of the neurotransmitter synthesis enzyme GAD67, which is expressed in inhibitory interneurons, are decreased in the dorsal and ventral forebrain of neonatal CBP+/− mice, indicating that CBP plays a role in regulating interneuron development in vivo. Thus, CBP normally acts to ensure the differentiation of appropriate numbers of forebrain interneurons, and when its levels are decreased, this causes deficits in interneuron development, providing a potential explanation for the epilepsy seen in individuals with RTS.