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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

USH patients are highly enriched in patients with two severe alleles. Patients with USH2A mutations were classified based on number of severe alleles (frameshift mutations, splicing site mutations and nonsense mutations). Enrichment of patients with two severe mutations is significant (Fisher exact test, p-value < 0.0001) in two independent USH patients cohorts (USH patients in this study [30]) compared to that of RP patients
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Fig4: USH patients are highly enriched in patients with two severe alleles. Patients with USH2A mutations were classified based on number of severe alleles (frameshift mutations, splicing site mutations and nonsense mutations). Enrichment of patients with two severe mutations is significant (Fisher exact test, p-value < 0.0001) in two independent USH patients cohorts (USH patients in this study [30]) compared to that of RP patients

Mentions: We identified 40 distinct USH2A alleles in this study. Previous studies from multiple groups, including ours, have already shown that mutations in USH2A can lead to either USH II or non-syndromic RP [10, 29]. We compared the USH2A alleles from 32 USH II patients identified in this paper with a collection of 38 RP patients whose disease was caused by USH2A mutations ([10] and our unpublished data). The number of obviously alleles (including nonsense mutations, splicing mutations, and frameshift mutations) carried by each patient was counted. As shown in Fig. 4, the vast majority of USH II patients carry at least one allele (29/32). Specifically, 17 patients carry two alleles and 12 USH II patients carry one allele. In contrast, among the 38 RP patients, only 2 carry two alleles and 12 carry one allele. Therefore, mutations carried by USH II patients tend to be more severe than those found in RP patients (Fisher’s exact test p-value < 0.0001). Indeed, patients with two severe mutations in USH2A were predominantly USH II patients (53 % USH II vs 5 % RP) while patients with two missense mutations were largely RP patients (9 % USH II vs 63 % RP). Further supporting our observations, the vast majority of USH2A alleles identified from another published USH II patient cohort are alleles (Fig. 4) [30]. It is likely that severe disruption of USH2A causes both hearing and RP phenotypes in most cases, while milder disruptions to USH2A only cause RP except in patients with a background or environment predisposed to hearing loss.Fig. 4


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)

USH patients are highly enriched in patients with two severe alleles. Patients with USH2A mutations were classified based on number of severe alleles (frameshift mutations, splicing site mutations and nonsense mutations). Enrichment of patients with two severe mutations is significant (Fisher exact test, p-value < 0.0001) in two independent USH patients cohorts (USH patients in this study [30]) compared to that of RP patients
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: USH patients are highly enriched in patients with two severe alleles. Patients with USH2A mutations were classified based on number of severe alleles (frameshift mutations, splicing site mutations and nonsense mutations). Enrichment of patients with two severe mutations is significant (Fisher exact test, p-value < 0.0001) in two independent USH patients cohorts (USH patients in this study [30]) compared to that of RP patients
Mentions: We identified 40 distinct USH2A alleles in this study. Previous studies from multiple groups, including ours, have already shown that mutations in USH2A can lead to either USH II or non-syndromic RP [10, 29]. We compared the USH2A alleles from 32 USH II patients identified in this paper with a collection of 38 RP patients whose disease was caused by USH2A mutations ([10] and our unpublished data). The number of obviously alleles (including nonsense mutations, splicing mutations, and frameshift mutations) carried by each patient was counted. As shown in Fig. 4, the vast majority of USH II patients carry at least one allele (29/32). Specifically, 17 patients carry two alleles and 12 USH II patients carry one allele. In contrast, among the 38 RP patients, only 2 carry two alleles and 12 carry one allele. Therefore, mutations carried by USH II patients tend to be more severe than those found in RP patients (Fisher’s exact test p-value < 0.0001). Indeed, patients with two severe mutations in USH2A were predominantly USH II patients (53 % USH II vs 5 % RP) while patients with two missense mutations were largely RP patients (9 % USH II vs 63 % RP). Further supporting our observations, the vast majority of USH2A alleles identified from another published USH II patient cohort are alleles (Fig. 4) [30]. It is likely that severe disruption of USH2A causes both hearing and RP phenotypes in most cases, while milder disruptions to USH2A only cause RP except in patients with a background or environment predisposed to hearing loss.Fig. 4

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