A Novel  Mutation Causing Alternative RNA Splicing in a Chinese Family With Branchio-Oto Syndrome: Implications for Molecular Diagnosis and Clinical Application

Anhai Chen; Jie Ling; Xin Peng; Xianlin Liu; Shuang Mao; Yongjia Chen; Mengyao Qin; Shuai Zhang; Yijiang Bai; Jian Song; Zhili Feng; Lu Ma; Dinghua He; Lingyun Mei; Chufeng He; Yong Feng

doi:10.21053/ceo.2023.00668

Clinical and Experimental Otorhinolaryngology (Nov 2023)

A Novel Mutation Causing Alternative RNA Splicing in a Chinese Family With Branchio-Oto Syndrome: Implications for Molecular Diagnosis and Clinical Application

Anhai Chen,
Jie Ling,
Xin Peng,
Xianlin Liu,
Shuang Mao,
Yongjia Chen,
Mengyao Qin,
Shuai Zhang,
Yijiang Bai,
Jian Song,
Zhili Feng,
Lu Ma,
Dinghua He,
Lingyun Mei,
Chufeng He,
Yong Feng

Affiliations

Anhai Chen: Department of Otorhinolaryngology, Xiangya Hospital, Central South University, Changsha, China
Jie Ling: Medical Functional Experiment Center, School of Basic Medicine, Central South University, Changsha, China
Xin Peng: National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Xianlin Liu: Department of Otorhinolaryngology, Xiangya Hospital, Central South University, Changsha, China
Shuang Mao: Department of Otorhinolaryngology, Xiangya Hospital, Central South University, Changsha, China
Yongjia Chen: Department of Otorhinolaryngology, Xiangya Hospital, Central South University, Changsha, China
Mengyao Qin: Department of Otorhinolaryngology, Xiangya Hospital, Central South University, Changsha, China
Shuai Zhang: Department of Otorhinolaryngology, Xiangya Hospital, Central South University, Changsha, China
Yijiang Bai: Department of Otorhinolaryngology, Xiangya Hospital, Central South University, Changsha, China
Jian Song: Department of Otorhinolaryngology, Xiangya Hospital, Central South University, Changsha, China
Zhili Feng: Department of Otorhinolaryngology, Head and Neck Surgery, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
Lu Ma: MOE Key Lab of Rare Pediatric Diseases and Institute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, China
Dinghua He: Department of Otorhinolaryngology, The Affiliated Maternal and Child Health Hospital of Hunan Province, Hengyang Medical School, University of South China, Changsha, China
Lingyun Mei: Department of Otorhinolaryngology, Xiangya Hospital, Central South University, Changsha, China
Chufeng He: Department of Otorhinolaryngology, Xiangya Hospital, Central South University, Changsha, China
Yong Feng: Department of Otorhinolaryngology, Xiangya Hospital, Central South University, Changsha, China

DOI: https://doi.org/10.21053/ceo.2023.00668
Journal volume & issue: Vol. 16, no. 4
pp. 342 – 358

Abstract

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Objectives. Branchio-oto syndrome (BOS) primarily manifests as hearing loss, preauricular pits, and branchial defects. EYA1 is the most common pathogenic gene, and splicing mutations account for a substantial proportion of cases. However, few studies have addressed the structural changes in the protein caused by splicing mutations and potential pathogenic factors, and several studies have shown that middle-ear surgery has limited effectiveness in improving hearing in these patients. BOS has also been relatively infrequently reported in the Chinese population. This study explored the genetic etiology in the family of a proband with BOS and provided clinical treatment to improve the patient’s hearing. Methods. We collected detailed clinical features and peripheral blood samples from the patients and unaffected individuals within the family. Pathogenic mutations were identified by whole-exome sequencing and cosegregation analysis and classified according to the American College of Medical Genetics and Genomics guidelines. Alternative splicing was verified through a minigene assay. The predicted three-dimensional protein structure and biochemical experiments were used to investigate the pathogenicity of the mutation. The proband underwent middle-ear surgery and was followed up at 1 month and 6 months postoperatively to monitor auditory improvement. Results. A novel heterozygous EYA1 splicing variant (c.1050+4 A>C) was identified and classified as pathogenic (PVS1(RNA), PM2, PP1). Skipping of exon 11 of the EYA1 pre-mRNA was confirmed using a minigene assay. This mutation may impair EYA1-SIX1 interactions, as shown by an immunoprecipitation assay. The EYA1-Mut protein exhibited cellular mislocalization and decreased protein expression in cytological experiments. Middle-ear surgery significantly improved hearing loss caused by bone-conduction abnormalities in the proband. Conclusion. We reported a novel splicing variant of EYA1 in a Chinese family with BOS and revealed the potential molecular pathogenic mechanism. The significant hearing improvement observed in the proband after middle-ear surgery provides a reference for auditory rehabilitation in similar patients.

Published in Clinical and Experimental Otorhinolaryngology

ISSN: 1976-8710 (Print); 2005-0720 (Online)
Publisher: Korean Society of Otorhinolaryngology-Head and Neck Surgery
Country of publisher: Korea, Republic of
LCC subjects: Medicine: Otorhinolaryngology
Website: https://www.e-ceo.org/

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