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BMC Med Genomics. 2019 Jan 28;12(1):28. doi: 10.1186/s12920-019-0475-x.

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

Author information

Department of Otolaryngology, Peking Union Medical College Hospital, Beijing, China.
Department of Medical Genetics, School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
College of Informatics, Huazhong Agricultural University, Wuhan, Hubei Province, China.
Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Department of Otolaryngology, Peking Union Medical College Hospital, Beijing, China.



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.


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.


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.


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


Association analysis; Next-generation sequencing; Severe microtia-atresia

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