Identification of sequence variants associated with severe microtia-astresia by targeted sequencing

Pu Wang,
Yibei Wang,
Xinmiao Fan,
Yaping Liu,
Yue Fan,
Tao Liu,
Chongjian Chen,
Shuyang Zhang†Email author and
Xiaowei Chen†Email author View ORCID ID profile

†Contributed equally

BMC Medical Genomics201912:28

https://doi.org/10.1186/s12920-019-0475-x

Received: 22 February 2018
Accepted: 14 January 2019
Published: 28 January 2019

Open Peer Review reports

Abstract

Background

Microtia-atresia is characterized by abnormalities of the auricle (microtia) and aplasia or hypoplasia of the external auditory canal, often associated with middle ear abnormalities. To date, no causal genetic mutations or genes have been identified in microtia-atresia patients.

Methods

We designed a panel of 131 genes associated with external/middle or inner ear deformity. Targeted genomic capturing combined with next-generation sequencing (NGS) was utilized to screen for mutations in 40 severe microtia-atresia patients. Mutations detected by NGS were filtered and validated. And then mutations were divided into three categories—rare or novel variants, low-frequency variants and common variants—based on their frequency in the public database. The rare or novel mutations were prioritized by pathogenicity analysis. For the low-frequency variants and common variants, we used association studies to explore risk factors of severe microtia-atresia.

Results

Sixty-five rare heterozygous mutations of 42 genes were identified in 27 (67.5%) severe microtia-atresia patients. Association studies to determine genes that were potentially pathogenic found that PLEC, USH2A, FREM2, DCHS1, GLI3, POMT1 and GBA genes were significantly associated with severe microtia-atresia. Of these, DCHS1 was strongly suggested to cause severe microtia-atresia as it was identified by both low-frequency and common variants association studies. A rare mutation (c.481C > T, p.R161C) in DCHS1 identified in one individual may be deleterious and may cause severe microtia-atresia.

Conclusion

We identified several genes that were significantly associated with severe microtia-atresia. The findings provide new insights into genetic background of external ear deformities.