title: CEP78is mutated in a distinct type of Usher syndrome.
abstract: 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.
  
  
  
  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 identifiedCEP78variants.
  
  
  
  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 geneCEP78. RT-PCR confirmed that the two variants indeed lead to abnormal splicing, resulting in premature stop of protein translation due to frameshift.
  
  
  
  Our results provide evidence thatCEP78is 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.
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.|Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Mingchu
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Chen
authors.affiliation: Ningxia Eye Hospital, People Hospital of Ningxia Hui Autonomous Region (First affiliated hospital of Northwest University for Nationalities), Yinchuan, Ningxia, China.
authors.forename: Xunlun
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Ningxia Eye Hospital, People Hospital of Ningxia Hui Autonomous Region (First affiliated hospital of Northwest University for Nationalities), Yinchuan, Ningxia, China.
authors.forename: Yani
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Huajin
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Zixi
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Ningxia Eye Hospital, People Hospital of Ningxia Hui Autonomous Region (First affiliated hospital of Northwest University for Nationalities), Yinchuan, Ningxia, China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Lizhu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Keqing
authors.initials: K
authors.lastname: Wang
authors.affiliation: Ningxia Eye Hospital, People Hospital of Ningxia Hui Autonomous Region (First affiliated hospital of Northwest University for Nationalities), Yinchuan, Ningxia, China.
authors.forename: Fangxia
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Sui
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
mesh_terms: D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D003241:Consanguinity; D059472:Exome / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D015894:Genome, Human; D006199:Hair Cells, Auditory, Inner / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008297:Male; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D052245:Usher Syndromes / Q000235:genetics* / Q000473:pathology
chemical_list: C000618001:CEP78 protein, human; D018797:Cell Cycle Proteins
keywords: CEP78; Usher syndrome; cone-rod dystrophy; next-generation sequencing