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Web End = Funct Integr Genomics (2016) 16:1317 DOI 10.1007/s10142-015-0462-z
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Exome sequencing identified FGF12 as a novel candidate gene for Kashin-Beck disease
Feng Zhang1 & Lanlan Dai2 & Weimin Lin3 & Wenyu Wang1 & Xuanzhu Liu2 &
Jianguo Zhang2 & Tielin Yang4 & Xiaogang Liu4 & Hui Shen5,6 & Xiangding Chen7 &
Lijun Tan7 & Qing Tian5,6 & Hong-Wen Deng5,6 & Xun Xu2 & Xiong Guo1
Received: 4 May 2015 /Revised: 30 July 2015 /Accepted: 2 August 2015 /Published online: 20 August 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract The objective of this study was to identify novel causal genes involved in the pathogenesis of Kashin-Beck disease (KBD). A representative grade III KBD sib pair with serious skeletal growth and development failure was subjected to exome sequencing using the Illumina Hiseq2000 platform. The detected gene mutations were then filtered against the data of 1000 Genome Project, dbSNP database, and BGI inhouse database, and replicated by a genome-wide association study (GWAS) of KBD. Ninety grade II or III KBD patients with extreme KBD phenotypes and 1627 healthy controls were enrolled in the GWAS. Affymetrix Genome-Wide Human SNP Array 6.0 was applied for genotyping. PLINK software was used for association analysis. We identified a novel 106T>C at the 3UTR of the FGF12 gene, which has not been reported by now. Sequence alignment observed high conversation at the mutated 3UTR+106T>C locus across various vertebrates. In the GWAS of KBD, we detected nine
SNPs of the FGF12 gene showing association evidence (P value<0.05) with KBD. The most significant association signal was observed at rs1847340 (P value=1.90105). This
study suggests that FGF12 was a susceptibility gene of KBD. Our results provide novel clues for revealing the pathogenesis of KBD and the biological function of FGF12.
Keywords Kashin-Beck disease . Exome sequencing . Genome-wide association study . Fibroblast growth factor
Introduction
Kashin-Beck Disease (KBD) is a chronic disabling osteochondropathy (Stone 2009). The primary clinical manifestations of KBD include pain, limited motion, and deformities of joints. In China, there are about 2.5 million KBD patients, and
Feng Zhang and Lanlan Dai...