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

Yu-Rong Lee; Yu-Chen Lin; Yi-Han Chang; Hsin-Yu Huang; Yi-Kai Hong; Wilson Jr F Aala; Wei-Ting Tu; Meng-Che Tsai; Yen-Yin Chou; Chao-Kai Hsu

doi:10.3389/fgene.2022.848879

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

Front Genet. 2022 Apr 8:13:848879. doi: 10.3389/fgene.2022.848879. eCollection 2022.

Authors

Yu-Rong Lee^{1

2}, Yu-Chen Lin^{1

3}, Yi-Han Chang^{1

4}, Hsin-Yu Huang¹, Yi-Kai Hong^{1

3}, Wilson Jr F Aala⁵, Wei-Ting Tu¹, Meng-Che Tsai⁶, Yen-Yin Chou⁶, Chao-Kai Hsu^{1

3

5}

Affiliations

¹ Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
² School of Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
³ International Center of Wound Repair and Regeneration, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁴ Education Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁵ Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁶ Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Abstract

Rubinstein-Taybi Syndrome (RSTS) is a rare congenital disease with distinctive facial features, broadening of the 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 diagnostic protocol by integrating multiplex ligation-dependent probe amplification (MLPA) and whole-exome sequencing (WES). Five patients clinically diagnosed with 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 as harboring a large heterozygous deletion in the 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 that identified causative genetic alterations in 4/5 of the patients, yielding a molecular diagnostic rate of 80%. Given the rarity of RSTS, more research is needed to explore its pathogenesis and mechanism.

Keywords: CREBBP (Crebb binding protein); genetic diagnosis; multiplex ligation-dependent probe amplification; next-generation sequencing; novel variant; rubinstein-taybi syndrome; whole-exome sequencing.