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