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CEP78 is mutated in a distinct type of Usher syndrome
  1. Qing Fu1,2,
  2. Mingchu Xu3,4,
  3. Xue Chen5,
  4. Xunlun Sheng6,
  5. Zhisheng Yuan1,
  6. Yani Liu6,
  7. Huajin Li1,
  8. Zixi Sun1,
  9. Huiping Li6,
  10. Lizhu Yang1,
  11. Keqing Wang3,4,
  12. Fangxia Zhang6,
  13. Yumei Li3,4,
  14. Chen Zhao5,
  15. Ruifang Sui1,
  16. Rui Chen3,4
  1. 1Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
  2. 2Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai, China
  3. 3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  4. 4Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA
  5. 5Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
  6. 6Ningxia Eye Hospital, People Hospital of Ningxia Hui Autonomous Region (First affiliated hospital of Northwest University for Nationalities), Yinchuan, Ningxia, China
  1. Correspondence to Dr Rui Chen, Department of Molecular and Human Genetics, Baylor College of Medicine, Room N1519, 1 Baylor Plaza, Houston, TX 77030, USA; ruichen{at}bcm.edu; Dr. Ruifang Sui, 1 Shuai Fu Yuan, Department of Ophthalmology Peking Union Medical College Hospital, Beijing 100730, P. R. China;hrfsui@163.com; Dr. Chen Zhao, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, P. R. China; dr_zhaochen@163.com

Abstract

Background Usher syndrome is a genetically heterogeneous disorder featured by combined visual impairment and hearing loss. Despite a dozen of genes involved in Usher syndrome having been identified, the genetic basis remains unknown in 20–30% of patients. In this study, we aimed to identify the novel disease-causing gene of a distinct subtype of Usher syndrome.

Methods Ophthalmic examinations and hearing tests were performed on patients with Usher syndrome in two consanguineous families. Target capture sequencing was initially performed to screen causative mutations in known retinal disease-causing loci. Whole exome sequencing (WES) and whole genome sequencing (WGS) were applied for identifying novel disease-causing genes. RT-PCR and Sanger sequencing were performed to evaluate the splicing-altering effect of identified CEP78 variants.

Results Patients from the two independent families show a mild Usher syndrome phenotype featured by juvenile or adult-onset cone–rod dystrophy and sensorineural hearing loss. WES and WGS identified two homozygous rare variants that affect mRNA splicing of a ciliary gene CEP78. RT-PCR confirmed that the two variants indeed lead to abnormal splicing, resulting in premature stop of protein translation due to frameshift.

Conclusions Our results provide evidence that CEP78 is a novel disease-causing gene for Usher syndrome, demonstrating an additional link between ciliopathy and Usher protein network in photoreceptor cells and inner ear hair cells.

  • Usher syndrome
  • cone-rod dystrophy
  • next-generation sequencing
  • CEP78

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