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Comprehensive molecular diagnosis of 67 Chinese Usher syndrome probands: high rate of ethnicity specific mutations in Chinese USH patients.

Jiang L, Liang X, Li Y, Wang J, Zaneveld JE, Wang H, Xu S, Wang K, Wang B, Chen R, Sui R - Orphanet J Rare Dis (2015)

Bottom Line: 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.By combining NGS-based molecular diagnosis and patient clinical information, a more accurate diagnosis, prognosis and personalized treatment of USH patients can be achieved.

View Article: PubMed Central - PubMed

Affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. jiang.lichun@foxmail.com.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Another sample figure title Summary of mutations identified in USH genes. a Genes mutated in USH I patients. b Genes mutated in USH II patients
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Fig2: Another sample figure title Summary of mutations identified in USH genes. a Genes mutated in USH I patients. b Genes mutated in USH II patients

Mentions: In this study, we recruited a total of 70 patients from 67 unrelated USH families from different regions of China. This group contained 14 patients diagnosed with USH type I, 54 patients as USH type II or USH type II-like, 1 patient as USH type III, and 1 patient with an undetermined subtype. In most families, the proband was the only affected member in the family, including three patients from consanguineous marriages (USHsrf2, USHsrf38, and USHsrf56) (Fig. 1). Two families, USHsrf24 and USHsrf66, have multiple affected members. In family USbHsrf24, both the father and the daughter were diagnosed with USH II. As shown in Fig. 1, the USHsrf66 family is a large family with five affected members, including USHsrf66, USHsrf68, and USHsrf59 who were recruited for this study. Detailed clinical information pertaining to these families is included in Additional file 1: Table S3. All our patients exhibited phenotypes consistent with USH syndrome [20]. All patients’ clinical phenotypes are listed in Additional file 1: Table S3, while representative fundus images and hearing test results are shown in Fig. 2.Fig. 1


Comprehensive molecular diagnosis of 67 Chinese Usher syndrome probands: high rate of ethnicity specific mutations in Chinese USH patients.

Jiang L, Liang X, Li Y, Wang J, Zaneveld JE, Wang H, Xu S, Wang K, Wang B, Chen R, Sui R - Orphanet J Rare Dis (2015)

Another sample figure title Summary of mutations identified in USH genes. a Genes mutated in USH I patients. b Genes mutated in USH II patients
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4559966&req=5

Fig2: Another sample figure title Summary of mutations identified in USH genes. a Genes mutated in USH I patients. b Genes mutated in USH II patients
Mentions: In this study, we recruited a total of 70 patients from 67 unrelated USH families from different regions of China. This group contained 14 patients diagnosed with USH type I, 54 patients as USH type II or USH type II-like, 1 patient as USH type III, and 1 patient with an undetermined subtype. In most families, the proband was the only affected member in the family, including three patients from consanguineous marriages (USHsrf2, USHsrf38, and USHsrf56) (Fig. 1). Two families, USHsrf24 and USHsrf66, have multiple affected members. In family USbHsrf24, both the father and the daughter were diagnosed with USH II. As shown in Fig. 1, the USHsrf66 family is a large family with five affected members, including USHsrf66, USHsrf68, and USHsrf59 who were recruited for this study. Detailed clinical information pertaining to these families is included in Additional file 1: Table S3. All our patients exhibited phenotypes consistent with USH syndrome [20]. All patients’ clinical phenotypes are listed in Additional file 1: Table S3, while representative fundus images and hearing test results are shown in Fig. 2.Fig. 1

Bottom Line: 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.By combining NGS-based molecular diagnosis and patient clinical information, a more accurate diagnosis, prognosis and personalized treatment of USH patients can be achieved.

View Article: PubMed Central - PubMed

Affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. jiang.lichun@foxmail.com.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus