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Identification of a CNGB1 Frameshift Mutation in a Han Chinese Family with Retinitis Pigmentosa

Xiang, Qin, PhD1,2; Guo, Yi, PhD2,3; Cao, Yanna, MD4; Xiong, Wei, PhD5; Deng, Xiong, RA2; Xu, Hongbo, MS2; Li, Yu, RA2; Du, Dongdong, MS6; Deng, Hao, PhD2,7*

doi: 10.1097/OPX.0000000000001305
ORIGINAL INVESTIGATIONS

SIGNIFICANCE Retinitis pigmentosa (RP) is a severe hereditary retinal disorder characterized by progressive degeneration of rod and cone photoreceptors. This study identified a novel frameshift mutation, c.385delC, p.(L129WfsTer148), in the cyclic nucleotide-gated channel beta 1 (CNGB1) gene of a consanguineous Han Chinese family with autosomal recessive RP (arRP). This expands the spectrum of CNGB1 gene variants in RP cases and possibly refines future genetic counseling.

PURPOSE The present study sought to identify potential pathogenetic gene mutations in a five-generation consanguineous Han Chinese family with RP.

METHODS Two members of a five-generation consanguineous Han Chinese pedigree with arRP and 100 normal individuals were enrolled in this study. Exome sequencing was performed on the 70-year-old male proband from a consanguineous family to screen potential pathogenic mutations according to the American College of Medical Genetics and Genomics for the interpretation of sequence variants. Sanger sequencing was performed on the proband, the proband's unaffected son, and 100 normal individuals to verify the disease-causing mutation.

RESULTS A novel frameshift mutation, c.385delC, p.(L129WfsTer148), with homozygous status in the CNGB1 gene was identified in the proband of the family with arRP, and the mutation with heterozygous status was carried by the asymptomatic son.

CONCLUSIONS The c.385delC (p.(L129WfsTer148)) mutation in the CNGB1 gene screened by exome sequencing is probably responsible for the RP phenotype in this family. The result expands the spectrum of CNGB1 gene variants in RP cases and possibly refines future genetic counseling.

1Postdoctoral Research Station of Basic Medicine, the Third Xiangya Hospital, Central South University, Changsha, China

2Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China

3Department of Medical Information, Information Security and Big Data Research Institute, Central South University, Changsha, China

4Department of Ophthalmology, the Third Xiangya Hospital, Central South University, Changsha, China

5Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China

6Novogene Co., Ltd., Beijing, China

7Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China *hdeng008@yahoo.com

Supplemental Digital Content: Appendix Figure A1, available at http://links.lww.com/OPX/A361. Depth distribution and mean sequencing depth in target regions of the proband. (A) Mean sequencing depth and proportion of covered bases of each chromosome. (B) Sequencing depth. 98.0% of target regions were covered with at least 10× coverage. 20× depth of coverage or more was achieved for 91.4% of target regions. Average sequencing depth was 56.25×.Appendix Table A1, available at http://links.lww.com/OPX/A362. General information on the exome sequencing output. Appendix Table A2, available at http://links.lww.com/OPX/A363. The prediction of the variant identified by exome sequencing and confirmed by Sanger sequencing according to ACMG guidelines.

Submitted: October 19, 2017

Accepted: July 15, 2018

Funding/Support: National Key Research and Development Program of China (2016YFC1306604; to HD); National Natural Science Foundation of China (81670216; to HD); Natural Science Foundation of Hunan Province (2015JJ4088 and 2016JJ2166; to HD); the New Xiangya Talent Project of the Third Xiangya Hospital of Central South University (20150301; to HD); Outstanding Youth Project of Hunan Provincial Education Department (17B194; to HD); and National-level College Students' Innovative Training Plan Program, China (201710533217 and 201710533227; to YL and HD).

Conflict of Interest Disclosure: The authors confirm that there are no conflicts of interest.

Author Contributions and Acknowledgments: Conceptualization: QX, HD; Data Curation: QX, HX, YL; Formal Analysis: YC; Investigation: YC; Methodology: YG, WX, XD; Resources: HD; Software: YG, WX, XD, HX, YL, DD; Supervision: HD; Writing – Original Draft: QX, YG; Writing – Review & Editing: HD.

The authors thank all the participating patients and investigators for their contributions to this research.

QX and YG contributed equally to this work.

Supplemental Digital Content: Direct URL links are provided within the text.

© 2018 American Academy of Optometry