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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

Double compound heterozygous mutations in patient USHsrf40. Patient USHsrf40 carries compound heterozygous mutations in two genes MYO7A and CGNA1: two missense mutation in MYO7A and frameshift and missense mutations in CNGA1. Mutations segregate in this family
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Fig3: Double compound heterozygous mutations in patient USHsrf40. Patient USHsrf40 carries compound heterozygous mutations in two genes MYO7A and CGNA1: two missense mutation in MYO7A and frameshift and missense mutations in CNGA1. Mutations segregate in this family

Mentions: Consistent with previous reports, we found that USH2A was the most frequently mutated gene in USH II patients, accounting for about 60 % (32 out of 54) of patients in this cohort. A total of 40 different mutations were identified in USH2A, including 27 novel alleles. The vast majority of the novel alleles (21/27) are clearly mutations, including frameshift, splice site, and nonsense mutations (Table 2). In addition, we identified 6 novel missense mutations predicted to be pathogenic (Table 2). It is worth noting that these novel mutations are mostly private and only two alleles, p.S2251X and p.1912_1912delfs, were observed in two probands. GPR98 is the second most frequently mutated gene in our USH II patients, with pathogenic mutations occurring in 3 patients. Two homozygous mutations in USH type III gene CLRN1 were found in 2 USH II patients. Compound heterozygous missense variants in USH type I gene MYO7A was identified in USH II patient USHsrf40, who carries two missense variants c.4951G > A: p.D1651N and c. 4360G > A: p.V1454I. Both of these variants are absent in the control database and segregate with disease in the family (Fig. 3). Novel homozygous splicing site mutation c.963 + 1G > A in DFNB31 was found in a USH II patient from a consanguineous family, which was confirmed by segregation tests.Fig. 3


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)

Double compound heterozygous mutations in patient USHsrf40. Patient USHsrf40 carries compound heterozygous mutations in two genes MYO7A and CGNA1: two missense mutation in MYO7A and frameshift and missense mutations in CNGA1. Mutations segregate in this family
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Double compound heterozygous mutations in patient USHsrf40. Patient USHsrf40 carries compound heterozygous mutations in two genes MYO7A and CGNA1: two missense mutation in MYO7A and frameshift and missense mutations in CNGA1. Mutations segregate in this family
Mentions: Consistent with previous reports, we found that USH2A was the most frequently mutated gene in USH II patients, accounting for about 60 % (32 out of 54) of patients in this cohort. A total of 40 different mutations were identified in USH2A, including 27 novel alleles. The vast majority of the novel alleles (21/27) are clearly mutations, including frameshift, splice site, and nonsense mutations (Table 2). In addition, we identified 6 novel missense mutations predicted to be pathogenic (Table 2). It is worth noting that these novel mutations are mostly private and only two alleles, p.S2251X and p.1912_1912delfs, were observed in two probands. GPR98 is the second most frequently mutated gene in our USH II patients, with pathogenic mutations occurring in 3 patients. Two homozygous mutations in USH type III gene CLRN1 were found in 2 USH II patients. Compound heterozygous missense variants in USH type I gene MYO7A was identified in USH II patient USHsrf40, who carries two missense variants c.4951G > A: p.D1651N and c. 4360G > A: p.V1454I. Both of these variants are absent in the control database and segregate with disease in the family (Fig. 3). Novel homozygous splicing site mutation c.963 + 1G > A in DFNB31 was found in a USH II patient from a consanguineous family, which was confirmed by segregation tests.Fig. 3

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