Comprehensive molecular diagnosis of 67 Chinese Usher syndrome probands: high rate of ethnicity specific mutations in Chinese USH patients.
BACKGROUND
Usher syndrome (USH) is the most common disease causing combined deafness and blindness. It is predominantly an autosomal recessive genetic disorder with occasionally digenic cases. Molecular diagnosis of USH patients is important for disease management. Few studies have tried to find the genetic cause of USH in Chinese patients. This study was designed to determine the mutation spectrum of Chinese USH patients.


METHODS
We applied next generation sequencing to characterize the mutation spectrum in 67 independent Chinese families with at least one member diagnosed with USH. Blood was collected at Peking Union Medical College Hospital. This cohort is one of the largest USH cohorts reported. We utilized customized panel and whole exome sequencing, variant analysis, Sanger validation and segregation tests to find disease causing mutations in these families.


RESULTS
We identified biallelic disease causing mutations in known USH genes in 70 % (49) of our patients. As has been previously reported, MYO7A is the most frequently mutated gene in our USH type I patients while USH2A is the most mutated gene in our USH type II patients. In addition, we identify mutations in CLRN1, DFNB31, GPR98 and PCDH15 for the first time in Chinese USH patients. Together, mutations in CLRN1, DNFB31, GPR98 and PCDH15 account for 11.4 % of disease in our cohort. Interestingly, although the spectrum of disease genes is quite similar between our Chinese patient cohort and other patient cohorts from different (and primarily Caucasian) ethnic backgrounds, the mutations themselves are dramatically different. In particular, 76 % (52/68) of alleles found in this study have never been previously reported. Interestingly, we observed a strong enrichment for severe protein truncating mutations expected to have severe functional consequence on the protein in USH II patients compared to the reported mutation spectrum in RP patients, who often carry partial protein truncating mutations.


CONCLUSIONS
Our study provides the first comprehensive genetic characterization of a large collection of Chinese USH patients. Up to 90 % of USH patients have disease caused by mutations in known USH disease genes. By combining NGS-based molecular diagnosis and patient clinical information, a more accurate diagnosis, prognosis and personalized treatment of USH patients can be achieved.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. jiang.lichun@foxmail.com.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. jiang.lichun@foxmail.com.
Lichun
L
Jiang
Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1 Shuai Fu Yuan, Beijing, 10073, China. xiaofangliang@aliyun.com.
Xiaofang
X
Liang
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. yumeil@bcm.edu.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. yumeil@bcm.edu.
Yumei
Y
Li
Department of Medical Genetics, School of Basic Medical Sciences, Capital Medical University, Beijing, China. jingwang@ccmu.edu.cn.
Jing
J
Wang
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. Zaneveld@bcm.edu.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. Zaneveld@bcm.edu.
Jacques Eric
JE
Zaneveld
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. hw11@bcm.edu.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. hw11@bcm.edu.
Hui
H
Wang
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. shanx@bcm.edu.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. shanx@bcm.edu.
Shan
S
Xu
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. keqingw@bcm.edu.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. keqingw@bcm.edu.
Keqing
K
Wang
Graduate School of Peking Union Medical College, Beijing, China. wbbahu@163.com.|National Research Institute for Family Planning, Beijing, China. wbbahu@163.com.
Binbin
B
Wang
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. ruichen@bcm.edu.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. ruichen@bcm.edu.|Structural and Computational Biology and Molecular Biophysics Program, Baylor College of Medicine, Houston, TX, 77030, USA. ruichen@bcm.edu.|Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA. ruichen@bcm.edu.
Rui
R
Chen
Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1 Shuai Fu Yuan, Beijing, 10073, China. hrfsui@163.com.
Ruifang
R
Sui
D002681:China; D015331:Cohort Studies; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D052245:Usher Syndromes / Q000175:diagnosis* / Q000208:ethnology / Q000235:genetics