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Mutations in human IFT140 cause non-syndromic retinal degeneration

Abstract

Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are two genetically heterogeneous retinal degenerative disorders. Despite the identification of a number of genes involved in LCA and RP, the genetic etiology remains unknown in many patients. In this study, we aimed to identify novel disease-causing genes of LCA and RP. Retinal capture sequencing was initially performed to screen mutations in known disease-causing genes in different cohorts of LCA and RP patients. For patients with negative results, we performed whole exome sequencing and applied a series of variant filtering strategies. Sanger sequencing was done to validate candidate causative IFT140 variants. Exome sequencing data analysis led to the identification of IFT140 variants in multiple unrelated non-syndromic LCA and RP cases. All the variants are extremely rare and predicted to be damaging. All the variants passed Sanger validation and segregation tests provided that the family members’ DNA was available. The results expand the phenotype spectrum of IFT140 mutations to non-syndromic retinal degeneration, thus extending our understanding of intraflagellar transport and primary cilia biology in the retina. This work also improves the molecular diagnosis of retinal degenerative disease.

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Acknowledgments

We thank all the patients and their family members for participating in this study. We thank the eyeGENE Working Group (https://nei.nih.gov/eyegene/staff_eyegene). The eyeGENE study was supported by the Department of Health and Human Services/National Institutes of Health/National Eye Institute intramural program under eyeGENE—Protocol 06-EI-0236 and 10-EI-N164 which has been funded in part under Contract No. HHS-N-260-2007-00001-C. We thank the Exome Aggregation Consortium and the groups that provided exome variant data. We thank Mr. Zachry T. Soens, Mr. Jason S. Salvo and Mr. Evan M. Jones for reviewing and editing the manuscript. NGS was conducted at the Functional Genomic Core (FGC) facility at Baylor College of Medicine supported by NIH shared instrument grant 1S10RR026550 to R. C. This work was supported by grants from National Eye Institute (R01EY022356, R01EY018571), Retinal Research Foundation, Foundation Fighting Blindness (BR-GE-0613-0618-BCM) to R. C. This study was also supported by grants from Foundation Fighting Blindness (CD-CL-0214-0631-PUMCH), National Natural Science Foundation of China (81470669) and Beijing Natural Science Foundation (7152116) to R. S. M. X. is supported by Cullen Foundation endowment to the Molecular and Human Genetics Graduate Program, Baylor College of Medicine. F. W. is supported by a predoctoral fellowship funded by the Burroughs Wellcome Trust Fund: The Houston Laboratory and Population Sciences Training Program in Gene Environment Interaction. Z. G. is supported by NIH T32 funding 2T32EY007102-21A1.

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Correspondence to Ruifang Sui or Rui Chen.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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The authors declare that they have no conflict of interest.

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M. Xu and L. Yang are co-first authors.

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Xu, M., Yang, L., Wang, F. et al. Mutations in human IFT140 cause non-syndromic retinal degeneration. Hum Genet 134, 1069–1078 (2015). https://doi.org/10.1007/s00439-015-1586-x

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Keywords

  • Retinitis Pigmentosa
  • Retinal Degeneration
  • Night Blindness
  • Peking Union Medical College Hospital
  • Retinitis Pigmentosa Patient