Clinical description and mutational profile of a Moroccan series of patients with Rubinstein Taybi syndrome
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ABSTRACT: 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.
SUBMITTER: Elalaoui S
PROVIDER: S-EPMC8568211 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant congenital disorder characterized by distinctive facial features, broad thumbs and halluces, growth retardation, and a variable degree of cognitive impairment. CREBBP is the major causative gene and mutations in EP300 are the cause of RTS in a minority of patients. In this study, 17 patients with a clinical diagnosis of RTS were investigated with direct sequencing, MLPA, and array-CGH in search for mutations in these two genes. Eleven patients (64.7%) had disease-causing point mutations or a deletion in CREBBP and in one patient (5.9%) a causal de novo frameshift mutation in EP300 was identified. This patient had broad thumbs, mild intellectual disability, and autism. In addition, an inherited missense mutation of uncertain clinical significance was identified in EP300 in one patient and his healthy father, and three patients had intronic nucleotide changes of uncertain clinical significance in CREBBP. Snoring and sleep apnea were common in both groups and four of the patients' mothers had preeclampsia during pregnancy. Importantly, difficulties associated with anesthesia were frequently reported and included delayed or complicated emergency in 53.3% of patients.
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Project description:BackgroundRubinstein-Taybi syndrome (RSTS) is a rare congenital malformation syndrome with clinical characteristics such as hypertrichosis, high arched eyebrows, large beaked nose, and broad thumbs and halluces. RSTS patients showed intellectual disability and health problems such as short stature, ophthalmologic abnormalities, congenital heart defects, genitourinary defects, and variable types of tumors. Although mutations in CREBBP and EP300 genes are associated with RSTS features, genetic causation is still unknown in 30% of patients.MethodsWe present clinical and molecular genetic characteristics of 25 unrelated Korean patients clinically diagnosed with RSTS. Sanger sequencing analysis and multiplex ligation-dependent probe amplification for CREBBP in 25 patients and exome sequencing of CREBBP-negative cases were performed in nine patients successively.ResultsCausative variants were identified in 20 (80%) patients: 16 (64%) in CREBBP and 4 (16%) in EP300. All the identified variants predict protein truncation (11 frameshift, 2 nonsense, 1 splicing-site, and 6 large intragenic deletions); there are no repeatedly identified sequence variants. Four of the CREBBP and all four EP300 variants are novel. Intellectual disability was noted in 24/25 patients (96%); no difference was found between CREBBP and EP300 groups. One patient with a CREBBP variant (4%) had malignant tumor.ConclusionsTo date, this is the largest cohort of patients with RSTS including EP300-related patients in Korea. Future large-scale studies to find genetic mutation of molecularly unsolved patients and long-term prospective studies are required to validate our results.
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Project description:Rubinstein-Taybi syndrome (RTS) is a rare genetic disorder with characteristic physical anomalies. It is characterized by mental retardation, postnatal growth deficiency, microcephaly, specific facial characteristics, broad thumbs, and big toes. Behavioral problems are common with RTS; they include mental retardation, impulsivity, distractibility, instability of mood, stereotypes, poor coordination, atypical depression, and mania. To date, there is lack of literature on the presence of schizophrenia or non-affective psychosis with RTS. Here, we describe two cases where there is co-morbid psychosis with RTS. One case is diagnosed as paranoid schizophrenia and the other as psychosis possibly schizophrenia. Genetic analysis was not done due to unavailability. The possible etiological factors for the association of psychosis with RTS are discussed. Factors such as regulators of RNA polymerase II and hypoxia-inducible factor 1 alpha (HIF1A) may be some common etiological factors for the association of schizophrenia or non-affective psychosis and RTS. Schizophrenia / non-affective psychosis can be a comorbid psychiatric condition with RTS.
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Project description:BackgroundRubinstein-Taybi syndrome (RSTS) is an extremely rare autosomal dominant genetic disease, with an estimated prevalence of one case per 125,000 live births. RSTS is characterized by typical facial features, microcephaly, broad thumbs and first toes, intellectual disability, and postnatal growth retardation. However, no standard diagnostic criteria are available for RSTS. In this review, we summarized the clinical features and genetic basis of RSTS and highlighted areas for future studies on an appropriate diagnostic protocol and follow-up care for RSTS.DiscussionRSTS is primarily characterized by delayed growth in height and weight, microcephaly, dysmorphic facial features, and broad thumbs and big toe. Over 90% RSTS individuals with disabilities survive to adulthood, but healthcare for these patients is particularly complex, time-consuming, and costly. In addition, no standard diagnostic criteria and follow-up care guidelines are available for RSTS. It has been shown that mutations in the genes encoding the cyclic-AMP-regulated enhancer binding protein (CREBBP) and the E1A-binding protein p300 (EP300) contributed to the development of RSTS. Therefore, genetic tests are useful for the diagnosis of RSTS, although most RSTS cases are currently diagnosed based on clinical features. The clinical features of RSTS have been extensively studied, which significantly contributes to the diagnosis of this extremely rare syndrome. However, the pathogenesis and genotype-phenotype associations of RSTS are largely unknown. Therefore, multicenter studies and international cooperation are highlighted for better understanding of this disease, establishing standard diagnostic criteria, and providing professional management and follow-up care of RSTS.
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