A novel CRX mutation by whole-exome sequencing in an autosomal dominant cone-rod dystrophy pedigree

• Published in: International journal of ophthalmology Vol. 8; no. 6; pp. 1112 - 1117
• Main Authors: Lu, Qin-Kang, Zhao, Na, Lv, Ya-Su, Gong, Wei-Kun, Wang, Hui-Yun, Tong, Qi-Hu, Lai, Xiao-Ming, Liu, Rong-Rong, Fang, Ming-Yan, Zhang, Jian-Guo, Du, Zhen-Fang, Zhang, Xian-Ning
• Format: Journal Article
• Language: English
• Published: China International Journal of Ophthalmology Press 18.12.2015; Press of International Journal of Ophthalmology (IJO PRESS)
• Subjects: autosomal dominant cone-rod dystrophy; Basic Research; cone-rod dystrophy; CRX gene; mutation; Sanger sequencing; whole-exome sequencing; autosomal dominant cone-rod dystrophy; mutation; cone-rod dystrophy; Sanger sequencing; whole-exome sequencing; CRX gene
• ISSN: 2222-3959; 2227-4898
• DOI: 10.3980/j.issn.2222-3959.2015.06.06

AIM: To identify the disease-causing gene mutation in a Chinese pedigree with autosomal dominant cone-rod dystrophy(ad CORD).· METHODS: A southern Chinese ad CORD pedigree including 9 affected individuals was studied. Whole-exome sequencing(WES), coupling the Agilent whole-exome capture system to the Illumina Hi Seq 2000 DNA sequencing platform was used to search the specific gene mutation in 3 affected family members and 1unaffected member. After a suggested variant was found through the data analysis, the putative mutation was validated by Sanger DNA sequencing of samples from all available family members.· RESULTS: The results of both WES and Sanger sequencing revealed a novel nonsense mutation c.C766T(p.Q256X) within exon 5 of CRX gene which was pathogenic for ad CORD in this family. The mutation could affect photoreceptor-specific gene expression with a dominant-negative effect and resulted in loss of the OTX tail, thus the mutant protein occupies the CRX-binding site in target promoters without establishing an interaction and, consequently, may block transactivation.·CONCLUSION: All modes of Mendelian inheritance in CORD have been observed, and genetic heterogeneity is a hallmark of CORD. Therefore, conventional genetic diagnosis of CORD would be time-consuming and laborintensive. Our study indicated the robustness and cost-effectiveness of WES in the genetic diagnosis of CORD.