Target sequencing of 307 deafness genes identifies candidate genes implicated in microtia

Abstract

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 <i>MUC4, MUC6, COL4A4, MYO7A, AKAP12, COL11A1, DSPP, ESPN, GPR98, PCDH15, BSN, CACNA1D, TPRN</i>, and <i>USH1C</i> for microtia (<i>P</i> = 2.51 × 10^-4). Among these genes, <i>COL4A4</i> and <i>COL11A1</i> may lead to microtia through focal adhesion pathway and ECM-receptor interaction pathway which are connected to the downstream <i>Wnt</i> 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.