Rubinstein-Taybi Syndrome. Genetic diagnosis of Rubinstein-Taybi Syndrome with Multiplex Ligation-dependent Probe Amplification (MLPA) and Whole Exome Sequencing (WES): A Case Series with 3 Novel CREBBP Variants

Rubinstein-Taybi Syndrome (RSTS) is a rare congenital disease with distinctive facial features, broad thumbs and halluces, and developmental delay. RSTS is caused by de novo genetic alterations in CREBBP and the homologous EP300 genes. In this study, we established a genetic diagnosis protocol by integrating multiplex ligation-dependent probe amplification (MLPA) and whole exome sequencing (WES). In total, five clinically diagnosed RSTS patients were enrolled for genetic testing. Total DNA was extracted from the peripheral blood of the patients and their family. One patient (Case 1) was identified to harbor a large heterozygous deletion in 16p13.3 of the CREBBP gene. Three patients (Cases 2-4) harbored different novel CREBBP variants (c.2608C>T:p.Gln870Ter, c.4404_4405del:p.Thr1468fs, c.3649C>T:p.Gln1217Ter), with high pathogenicity scores. No causative variants were identified for the fifth RSTS patient (Case 5). Here, we here propose a molecular diagnostic protocol which identified causative genetic alterations in 4/5 of the patients yielding a molecular diagnostic rate of 80%. Given the rarity of the disease, more research is indeed needed to explore the pathogenesis and mechanism of RSTS.