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Genetic and clinical heterogeneity in Korean patients with Rubinstein-Taybi syndrome.

ABSTRACT:

Background

Rubinstein-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.

Methods

We 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.

Results

Causative 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.

Conclusions

To 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.

SUBMITTER: Choi N

PROVIDER: S-EPMC8580098 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rubinstein-Taybi syndrome (RSTS) is a rare genetic disorder in humans characterized by growth and psychomotor delay, abnormal gross anatomy, and mild to severe mental retardation (Rubinstein and Taybi, Am J Dis Child 105:588-608, 1963, Hennekam et al., Am J Med Genet Suppl 6:56-64, 1990). RSTS is caused by de novo mutations in epigenetics-associated genes, including the cAMP response element-binding protein (CREBBP), the gene-encoding protein referred to as CBP, and the EP300 gene, which encodes the p300 protein, a CBP homologue. Recent studies of the epigenetic mechanisms underlying cognitive functions in mice provide direct evidence for the involvement of nuclear factors (e.g., CBP) in the control of higher cognitive functions. In fact, a role for CBP in higher cognitive function is suggested by the finding that RSTS is caused by heterozygous mutations at the CBP locus (Petrij et al., Nature 376:348-351, 1995). CBP was demonstrated to possess an intrinsic histone acetyltransferase activity (Ogryzko et al., Cell 87:953-959, 1996) that is required for CREB-mediated gene expression (Korzus et al., Science 279:703-707, 1998). The intrinsic protein acetyltransferase activity in CBP might directly destabilize promoter-bound nucleosomes, facilitating the activation of transcription. Due to the complexity of developmental abnormalities and the possible genetic compensation associated with this congenital disorder, however, it is difficult to establish a direct role for CBP in cognitive function in the adult brain. Although aspects of the clinical presentation in RSTS cases have been extensively studied, a spectrum of symptoms found in RSTS patients can be accessed only after birth, and, thus, prenatal genetic tests for this extremely rare genetic disorder are seldom considered. Even though there has been intensive research on the genetic and epigenetic function of the CREBBP gene in rodents, the etiology of this devastating congenital human disorder is largely unknown.