BMPR1B mutation causes Pierre Robin sequence

// Yongjia Yang 1,2,* , Jianying Yuan 1,3,* , Xu Yao 1 , Rong Zhang 1,4 , Hui Yang 1,4 , Rui Zhao 1 , Jihong Guo 1,5 , Ke Jin 1 , Haibo Mei 1 , Yongqi Luo 1 , Liu Zhao 1 , Ming Tu 1 and Yimin Zhu 1,2 1 The Laboratory of Genetics and Metabolism, Hunan Children’s Research Institute , Hunan Children’s Hospital, University of South China, Changsha, China 2 Institute of Emergency Medicine, People’s Hospital of Hunan Province, Changsha, China 3 BGI-Shenzhen, Shenzhen, China 4 Division of Neonatology, Hunan Children’s Hospital, University of South China, Changsha, China 5 State Key Laboratory of Medical Genetics, Central South University, Changsha, China * These authors have contributed equally to this work Correspondence to: Yimin Zhu, email: // Keywords : BMPR1B, Pierre Robin sequence, gene fusion, BMP signalling, cleft palate, Chromosome Section Received : January 05, 2017 Accepted : February 27, 2017 Published : March 23, 2017 Abstract Background: We investigated a large family with Pierre Robin sequence (PRS). Aim of the study: This study aims to determine the genetic cause of PRS. Results: The reciprocal translocation t(4;6)(q22;p21) was identified to be segregated with PRS in a three-generation family. Whole-genome sequencing and Sanger sequencing successfully detected breakpoints in the intragenic regions of BMRP1B and GRM4 . We hypothesized that PRS in this family was caused by (i) haploinsufficiency for BMPR1B or (ii) a gain of function mechanism mediated by the BMPR1B - GRM4 fusion gene. In an unrelated family, we identified another BMPR1B -splicing mutation that co-segregated with PRS. Conclusion: We detected two BMPR1B mutations in two unrelated PRS families, suggesting that BMPR1B disruption is probably a cause of human PRS. Methods: GTG banding, comparative genomic hybridization, whole-genome sequencing, and Sanger sequencing were performed to identify the gene causing PRS.