Clinical description and mutational profile of a Moroccan series of patients with Rubinstein Taybi syndrome

Background: Rubinstein-Taybi syndrome (RSTS; OMIM 180849) is a rare autosomal dominant developmental disorder with an estimated prevalence of one case per 125,000 live births. RSTS is characterized by typical face, broad thumbs and halluces, short stature, and intellectual disability. Facial dysmorphy is characteristic with microcephaly, low frontal hairline, arched eyebrows, long eyelashes, convex profile of nose, narrow palate, and micrognathia. RSTS is mainly due to mutations or microdeletions of the CREBBP gene (about 60%) and more rarely of the EP300 gene (8%). Objective: Clinical description and identification of mutations of patients with Rubinstein Taybi syndrome. Methods: PCR and direct sequencing of CREBBP gene. Results: We report here, the clinical and molecular data of a series of six Moroccan patients with a phenotype of RSTS. The molecular study of the major gene CREBBP (by Sanger Sequencing followed by CGH array, if sequence normal) revealed point mutations in five patients. For the sixth patient, CGH array revealed a microdeletion carrying the CREBBP gene. Through this work, we emphasize the importance of clinical expertise in the diagnosis, management and genetic counseling in Rubinstein Taybi syndrome. Keywords: Rubinstein Taybi syndrome; CREBBP gene; mutation; Moroccan.

Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

The Rubinstein-Taybi syndrome (RSTS) is a rare congenital developmental disorder characterized by a typical facial dysmorphism, distal limb abnormalities, intellectual disability, and many additional phenotypical features. It occurs at between 1/100,000 and 1/125,000 births. Two genes are currently known to cause RSTS, CREBBP and EP300, mutated in around 55% and 8% of clinically diagnosed cases, respectively. To date, 500 pathogenic variants have been reported for the CREBBP gene and 118 for EP300. These two genes encode paralogs acting as lysine acetyltransferase involved in transcriptional regulation and chromatin remodeling with a key role in neuronal plasticity and cognition. Because of the clinical heterogeneity of this syndrome ranging from the typical clinical diagnosis to features overlapping with other Mendelian disorders of the epigenetic machinery, phenotype/genotype correlations remain difficult to establish. In this context, the deciphering of the patho-physiological process underlying these diseases and the definition of a specific episignature will likely improve the diagnostic efficiency but also open novel therapeutic perspectives. This review summarizes the current clinical and molecular knowledge and highlights the epigenetic regulation of RSTS as a model of chromatinopathy.

Mutation in the CREBBP Gene in the Girl with Toe Walking Syndrome: Clinical Case

Background. Pathogenic variants of the CREBBP gene have been revealed in patients with Rubinstein–Taybi and Menke–Hennekam syndromes, however, the toe walking symptom was not mentioned in these pathologies.Clinical Case Description. The pathogenic nucleotide variant c.5600G>A in heterozygous state in the CREBBP gene was revealed in our 9-year-old female patient with refractory toe walking and developmental speech delay. There were no abnormalities typical for Rubinstein–Taybi syndrome, but there were several signs of Menke–Hennekam syndrome.Conclusion. The genetic anomaly associated with toe walking is described. This observation allows us to critically relate to the hypothesis about the idiopathic genesis of this form of gait disorder at the absence of obvious neurological or orthopedic causes of its development.

New point mutation in CREBBP Gene cause Rubinstein-Taybi syndrome: A case report

Background: RSTS is a rare autosomal dominant inheritance disease. It is easy to overlap with the phenotypes of other syndromes, To assist with future diagnoses, we summarize the clinical and genetic characteristics of children with Rubinstein-Taybi syndrome. Case presentation: The patient, female, aged 3 months, 4.2 kg, was admitted into our hospital 3 times after birth due to repeated infections, shortness of breath, poor response, low crying, cyanosis and poor breastfeeding. The child has a special complexion with congenital heart disease, hearing impairment, and hypothyroidism. The anterior fontanel has a lot of vellus hair, mainly on the back, low hairline, micrognathia, high palate arch. the high-precision clinical explicit PLUS test and analysis were performed on all of their blood. CREBBP gene heterozygous mutation c.890T> A (p.L297 *) was detected. At the same time, the sequencing data showed that the parents of the examinee did not carry this mutation, which may be new. Conclusion: combining clinical manifestations and genetic testing can clearly diagnose Rubinstein-Taybi syndrome and enriched human CREBBP gene mutation database.

Deletion of SHANK3 and CREBBP gene in the patients with intellectual disability and mix phenotype

Rubinstein-Taybi Syndrome (RSTS) as a group of congenital anomalies mainly include, short broad thumbs and toes, short stature and intellectual disability are caused by either a micro-deletion in the CREBBP (CBP) or EP300 genes. Generally most RSTS patients have a deletion in the CREBBP gene but some patients have shown deletion in the EP300 gene. Here we introduce an affected case without some typical characteristics of RSTS with deletions in the CREBBP and SHANK3 genes. The patient was a 24 years old man with a history of infantile hypotonia and childhood developmental delay, heavy eyebrows, ptosis, speech difficulty without large thumb and toes. The conventional cytogenetic finding was normal male. Further investigation was performed using Multiplex Ligation Probe Amplification (MLPA) technique to screen micro-deletion syndromes and subtelomeric rearrangements and Micro-deletion was detected in CREBBP and SHANK3 gene and a detected in DECR2 gene. Deletion in the CREBBP or EP300 genes or both in the patients with broad thumb and toes (RSTS) has been detected but there are other patients with deletion in CREBBP gene without this sign of RSTS. However, we report SHANK3 gene deletion in the patient with deletion in CREBBP gene and without broad thumbs and toes. Keywords: Rubinstein-Taybi Syndrome (RSTS); CREBBP; SHANK3; Broad thumb and toes

Genetic polymorphism and transcriptional regulation of CREBBP gene in patient with diffuse large B-cell lymphoma

In the present study, we aim to examine the relationship between genetic polymorphism and transcriptional expression of cyclic AMP response element binding protein (CREBBP) and the risk of diffuse large B-cell lymphoma (DLBCL). Two hundred and fifty healthy individuals and 248 DLBCL patients participated in the present study. The CREBBP rs3025684 polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The mRNA expression of CREBBP was tested by the real-time quantitative PCR (RT-qPCR). The allele A frequency of CREBBP rs3025684 in DLBCL patients was obviously higher than that of controls (P=0.01). No significant difference was detected between CREBBP rs3025684 polymorphism and clinical characteristics of DLBCL patients when subgrouped according to different parameters. The results demonstrated that the allele A of CREBBP rs3025684 increased the susceptibility to DLBCL (P=0.004), with a worse overall survival (OS) rate (P=0.002), a worse progression-free survival (PFS) rate (P=0.033) and poor prognosis (P=0.003) in DLCBL patients. Furthermore, the expression of CREBBP mRNA was considerably decreased in DLBCL patients as compared with controls (P<0.001), and the expression in patients with GG genotype was up-regulated in comparison with patients with GA and AA genotype (P=0.016 and P=0.001, respectively). However, no statistical differences were found in OS (P=0.201) and PFS (P=0.353) between the lower CREBBP mRNA level subgroup and higher CREBBP mRNA level subgroup. These data suggested that the CREBBP gene may be an important prognostic factor in DLBCL patients and perform an essential function in the development of DLBCL.