Target sequencing of 307 deafness genes identifies candidate genes implicated in microtia
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Pu Wang1, Xinmiao Fan1, Yibei Wang1, Yue Fan1, Yaping Liu2, Shuyang Zhang3 and Xiaowei Chen1
1Department of Otolaryngology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
2Department of Medical Genetics, School of Basic Medicine, Peking Union Medical College, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
3Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
Xiaowei Chen, email: [email protected]
Shuyang Zhang, email: [email protected]
Keywords: microtia, deafness genes, next-generation sequencing, SKAT
Received: April 23, 2017 Accepted: May 29, 2017 Published: June 28, 2017
Microtia is a congenital malformation of the external ear caused by genetic and/or environmental factors. However, no causal genetic mutations have been identified in isolated microtia patients. In this study, we utilized targeted genomic capturing combined with next-generation sequencing to screen for mutations in 307 deafness genes in 32 microtia patients. Forty-two rare heterozygous mutations in 25 genes, including 22 novel mutations in 24 isolated unilateral microtia cases were identified. Pathway analysis found five pathways especially focal adhesion pathway and ECM-receptor interaction pathway were significantly associated with microtia. The low-frequency variants association study was used and highlighted several strong candidate genes MUC4, MUC6, COL4A4, MYO7A, AKAP12, COL11A1, DSPP, ESPN, GPR98, PCDH15, BSN, CACNA1D, TPRN, and USH1C for microtia (P = 2.51 × 10-4). Among these genes, COL4A4 and COL11A1 may lead to microtia through focal adhesion pathway and ECM-receptor interaction pathway which are connected to the downstream Wnt signaling pathway. The present results indicate that certain genes may affect both external/middle and inner ear development, and demonstrate the benefits of using a capture array in microtia patients.
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