Genetic Diagnosis of Rubinstein-Taybi Syndrome with Multiplex Ligation-dependent Probe Amplification (MLPA) and Whole Exome Sequencing (WES): Case Series with a Novel CREBBP Variant. undefined

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 patients clinically diagnosed of RSTS were enrolled for genetic testing. Germline DNA was extracted from the peripheral blood of the patients and their families. One patient (Case 1) was identified to harbor a large heterozygous deletion in 16p13.3 region, spanning the CREBBP gene. Three patients (Cases 2-4) harbored different CREBBP variants (c.2608C>T:p.Gln870Ter, c.4404_4405del:p.Thr1468fs, c.3649C>T:p.Gln1217Ter). No causative variants were identified for the fifth RSTS patient (Case 5). Here, we 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.