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Ruifang Sui, Fangtian Dong, Lichun Jiang, Xiaofang Liang, Eric Zaneveld, Yumei Li, Rui Chen; Comprehensive molecular diagnosis of 70 representative Chinese Usher syndrome patients from 67 families: high rate of novel mutations in Chinese USH patients. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1245.
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© ARVO (1962-2015); The Authors (2016-present)
Usher syndrome (USH) is the most common condition of combined deafness and blindness. It is an autosome recessive genetic disorder. Molecular diagnosis of USH patients is important for disease management. Few studies have tried to find the genetic cause of USH in Chinese patients. The purpose of this study is to determine the mutation spectrum of Chinese USH patients and to analyze genotype-phenotype correlation.
Next generation sequencing was applied to characterize the mutation spectrum of 70 representative patients from a total of 67 independent families diagnosed with USH from China collected by Peking Union Medical College Hospital and it is one of the largest USH cohorts reported.We utilized customized panel and whole exome sequencing, variant analysis, Sanger validation, segregation test, and genotype phenotype analysis.
We identified biallelic mutations in known USH genes in 70% (49) of our representative patients. As has previously reported, MYO7A is the most frequently mutated gene for USH type I patients while USH2A is the most frequently mutated gene for USH type II patients. In addition, we identified mutations in CLRN1, DFNB31, GPR98 and PCDH15 first time in Chinese USH patients. Together mutations in these genes account for 11.4% in our cohort. Interestingly, although spectrum of disease genes is quite similar between our Chinese patient cohorts and other patient cohorts from different (and primarily Caucasian) ethnicity backgrounds, the mutations themselves are dramatically different. In particular 76% (52/68) of alleles found in this study has never been previously reported. Leveraging the large number of USH2A mutant alleles identified, we associated these new genotypes with their corresponding phenotypes. We observed strong enrichment of severe loss of function mutations in USH patients compared to the reported mutation spectrum in RP patients, who often carry partial loss of function alleles.<br />
Our study provides the first comprehensive characterization of a large collection of Chinese USH patients, providing additional insights into the disease at the molecular level.<br />
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