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 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.

Highlights

  • Microtia is a congenital developmental malformation of the external ear that ranges in severity from mild differences in auricular shape and size to complete absence of the external ear with atresia or stenosis of the auditory canal [1,2]

  • COL4A4 and COL11A1 may lead to microtia through focal adhesion pathway and extracellular matrix (ECM)-receptor interaction pathway which are connected to the downstream Wnt signaling pathway

  • Using a rigorous filtering pipeline, we identified 42 very rare heterozygous mutations, including 22 novel mutations in 25 genes from 24 isolated unilateral microtia patients (Table 1)

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Summary

Introduction

Microtia is a congenital developmental malformation of the external ear that ranges in severity from mild differences in auricular shape and size to complete absence of the external ear with atresia or stenosis of the auditory canal [1,2]. Prevalence rates of this uncommon anomaly have been reported to vary from 0.83 to 4.34 per 10,000 [3]. In grade I microtia, all of the outer ear structures are normal, but the pinna is small This can occur with or without aural atresia. Grade IV is the extreme case in which the external ear and auditory canal are absent, a condition called anotia [7]

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