Mutation analysis of the ATP7B gene and genotype-phenotype correlation in Chinese patients with Wilson disease

Abstract AIM To discover the novel ATP7B mutations in 103 southern Chinese patients with Wilson disease (WD), and to determine the spectrum and frequency of mutations in the ATP7B gene and genotype-phenotype correlation in a large-scale sample of Chinese WD patients. Methods One hundred three WD patients from 101 unrelated families in southern China were enrolled in this study. Genomic DNA was extracted from the peripheral blood. Direct sequencing of all 21 exons within ATP7B was performed. Subsequently, an extensive study of the overall spectrum and frequency of ATP7B mutations and genotype-phenotype correlation was performed in all Chinese patients eligible from the literature, combined with the current southern group.Results In 103 patients with WD, we identified 48 different mutations (42 missense mutations, 4 nonsense mutations and 2 frameshifts). Of these, 7 mutations had not been previously reported: 1510_1511insA, 2075T>C (Leu692Pro), 2233C>A (Leu745Met), 3209C>G (Pro1070Arg),3677C>T (Thr1226Ile), 3793G>T (Val1265Leu) and 3824T>C (Leu1275Ser). The 2333G>T (Arg778 Leu) at exon 8, was the most common mutation with an allelic frequency of 18.8%, followed by 2975C>T (Pro992Leu) at exon 13, with an allelic frequency of 13.4%. In the comprehensive study, 233 distinct mutations were identified, including 154 missense mutations, 23 nonsense mutations and 56 frameshifts. Eighty-five variants were identified as novel mutations. The 2333G>T (Arg778 Leu) and 2975C>T (Pro992Leu) were the most common mutations, with allelic frequencies of 28.6% and 13.0%, respectively. Exons 8, 12, 13, 16 and 18 were recognised as hot spot exons. Phenotype-genotype correlation analysis suggested that 2333G>T (Arg778 Leu) was significantly associated with lower levels of serum ceruloplasmin (P=0.034). 2975C>T (Pro992Leu) was correlated with earlier age of disease onset (P=0.002). Additionally, we found that the 3809A>G (Asn1270Ser) mutation significantly indicated younger onset age (P=0.012), and the 3884C>T (Ala1295Val) mutation at exon 18 was significantly associated with hepatic presentation (P=0.048). Moreover, the patients with mixed presentation displayed the initial WD features at an older onset age than the groups with either liver disease or neurological presentation (P=0.039, P=0.015, respectively). No significant difference was observed in the presence of KF rings among the three groups with different clinical manifestations. Conclusion In this study, we identified seven novel mutations in 103 WD patients from the southern part of China, which could enrich the previously established mutational spectrum of the ATP7B gene. Moreover, we tapped into a large-scale study of a Chinese WD cohort to characterise the overall phenotypic and genotypic spectra and assess the association between genotype and phenotype, which enhances the current knowledge about the population genetics of WD in China.

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Mutation analysis of the ATP7B gene and genotype–phenotype correlation in Chinese patients with Wilson disease

BMC Gastroenterology ◽

10.1186/s12876-021-01911-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Mingming Li ◽

Jing Ma ◽

Wenlong Wang ◽

Xu Yang ◽

Kaizhong Luo

Keyword(s):

Wilson Disease ◽

Large Scale ◽

Allelic Frequency ◽

Chinese Patients ◽

Missense Mutations ◽

Onset Age ◽

Phenotype Correlation ◽

Novel Mutations ◽

Nonsense Mutations ◽

Genotype Phenotype Correlation

Abstract Aim To discover the novel ATP7B mutations in 103 southern Chinese patients with Wilson disease (WD), and to determine the spectrum and frequency of mutations in the ATP7B gene and genotype–phenotype correlation in a large-scale sample of Chinese WD patients. Methods One hundred three WD patients from 101 unrelated families in southern China were enrolled in this study. Genomic DNA was extracted from the peripheral blood. Direct sequencing of all 21 exons within ATP7B was performed. Subsequently, an extensive study of the overall spectrum and frequency of ATP7B mutations and genotype–phenotype correlation was performed in all Chinese patients eligible from the literature, combined with the current southern group. Results In 103 patients with WD, we identified 48 different mutations (42 missense mutations, 4 nonsense mutations and 2 frameshifts). Of these, 3 mutations had not been previously reported: c.1510_1511insA, c.2233C>A (p.Leu745Met) and c.3824T>C (p.Leu1275Ser). The c.2333G>T (p.Arg778 Leu) at exon 8, was the most common mutation with an allelic frequency of 18.8%, followed by c.2975C>T (p.Pro992Leu) at exon 13, with an allelic frequency of 13.4%. In the comprehensive study, 233 distinct mutations were identified, including 154 missense mutations, 23 nonsense mutations and 56 frameshifts. Eighty-five variants were identified as novel mutations. The c.2333G>T (p.Arg778 Leu) and c.2975C>T (p.Pro992Leu) were the most common mutations, with allelic frequencies of 28.6% and 13.0%, respectively. Exons 8, 12, 13, 16 and 18 were recognised as hotspot exons. Phenotype–genotype correlation analysis suggested that c.2333G>T (p.Arg778 Leu) was significantly associated with lower levels of serum ceruloplasmin (P = 0.034). c.2975C>T (p.Pro992Leu) was correlated with earlier age of disease onset (P = 0.002). Additionally, we found that the c.3809A>G (p.Asn1270Ser) mutation significantly indicated younger onset age (P = 0.012), and the c.3884C>T (p.Ala1295Val) mutation at exon 18 was significantly associated with hepatic presentation (P = 0.048). Moreover, the patients with mixed presentation displayed the initial WD features at an older onset age than the groups with either liver disease or neurological presentation (P = 0.039, P = 0.015, respectively). No significant difference was observed in the presence of KF rings among the three groups with different clinical manifestations. Conclusion In this study, we identified three novel mutations in 103 WD patients from the southern part of China, which could enrich the previously established mutational spectrum of the ATP7B gene. Moreover, we tapped into a large-scale study of a Chinese WD cohort to characterise the overall phenotypic and genotypic spectra and assess the association between genotype and phenotype, which enhances the current knowledge about the population genetics of WD in China.

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Spectrum of ATP7B mutations and genotype-phenotype correlation in large-scale Chinese patients with Wilson Disease

Clinical Genetics ◽

10.1111/cge.12951 ◽

2017 ◽

Vol 92 (1) ◽

pp. 69-79 ◽

Cited By ~ 12

Author(s):

N. Cheng ◽

H. Wang ◽

W. Wu ◽

R. Yang ◽

L. Liu ◽

...

Keyword(s):

Wilson Disease ◽

Large Scale ◽

Chinese Patients ◽

Phenotype Correlation ◽

Genotype Phenotype Correlation

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Novel mutations of RPGR in Chinese families with X-linked retinitis pigmentosa

BMC Ophthalmology ◽

10.1186/s12886-019-1250-7 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Zhimeng Zhang ◽

Hehua Dai ◽

Lei Wang ◽

Tianchang Tao ◽

Jing Xu ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Mutation Screening ◽

Phenotype Correlation ◽

Novel Mutations ◽

Pathological Myopia ◽

Nonsense Mutations ◽

Chinese Families ◽

Coding Regions ◽

Genotype Phenotype Correlation ◽

Male Patients

Abstract Background RP (retinitis pigmentosa) is a group of hereditary retinal degenerative diseases. XLRP is a relatively severe subtype of RP. Thus, it is necessary to identify genes and mutations in patients who present with X-linked retinitis pigmentosa. Methods Genomic DNA was extracted from peripheral blood. The coding regions and intron-exon boundaries of the retinitis pigmentosa GTPase regulator (RPGR) and RP2 genes were amplified by PCR and then sequenced directly. Ophthalmic examinations were performed to identify affected individuals from two families and to characterize the phenotype of the disease. Results Mutation screening demonstrated two novel nonsense mutations (c.1541C > G; p.S514X and c.2833G > T; p.E945X) in the RPGR gene. The clinical manifestation of family 1 with mutations in exon 13 was mild. Genotype-phenotype correlation analysis suggested that patients with mutations close to the downstream region of ORF15 in family 2 manifested an early loss of cone function. Family 2 carried a nonsense mutation in ORF15 that appeared to have a semi-dominant pattern of inheritance. All male patients and two female carriers in family 2 manifested pathological myopia (PM), indicating that there may be a distinctive X-linked genotype-phenotype correlation between RP and PM. Conclusions We identified two novel mutations of the RPGR gene, which broadens the spectrum of RPGR mutations and the phenotypic spectrum of the disease in Chinese families.

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21-Hydroxylase deficiency-induced congenital adrenal hyperplasia in 230 Chinese patients: Genotype–phenotype correlation and identification of nine novel mutations

Steroids ◽

10.1016/j.steroids.2016.01.007 ◽

2016 ◽

Vol 108 ◽

pp. 47-55 ◽

Cited By ~ 16

Author(s):

Ruifang Wang ◽

Yongguo Yu ◽

Jun Ye ◽

Lianshu Han ◽

Wenjuan Qiu ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Chinese Patients ◽

Adrenal Hyperplasia ◽

Phenotype Correlation ◽

Novel Mutations ◽

Hydroxylase Deficiency ◽

Genotype Phenotype Correlation ◽

21 Hydroxylase Deficiency

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A Genotype-Phenotype Correlation of Haemophilia a in Victorian Patients with a Description of Novel Mutations

Blood ◽

10.1182/blood-2018-99-112721 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2498-2498

Author(s):

Shreerang Sirdesai ◽

Kerryn Weekes ◽

Asif Alam ◽

Huyen A Tran ◽

Christopher Barnes ◽

...

Keyword(s):

In Silico ◽

Family Members ◽

In Silico Analysis ◽

Clinical Severity ◽

Missense Mutations ◽

Phenotype Correlation ◽

Novel Mutations ◽

Mild Phenotype ◽

Genotype Phenotype Correlation ◽

Silico Analysis

Abstract Aim: Hemophilia A (HA) is caused by abnormalities in the Factor VIII gene. Certain abnormalities correlate with disease severity. Here, we report the genotype-phenotype correlation for all Victorian HA patients. Methods: Using the Australian Bleeding Disorders Registry, Victorian HA patients were identified. All genetic testing was conducted at Southern Health. The testing algorithm is summarized in Figure 1. Mutations were compared with the list of known Factor 8 mutations on the Champ and EAHAD F8 Variant Databases. A PubMed search was undertaken for any mutations not on either database. If this too was unrevealing, the mutation was designated novel. In-silico analysis was conducted on all novel mutations using three open-access, online prediction tools: a) Mutation Taster; b) Poly-Phen 2; c) Human Splice Site Predictor. Results: 318 patients with matched clinical and genetic records were identified. 275 had known FVIII mutations and 36 novel FVIII mutations were discovered. Eight patients (3%) had no mutations identified. (Table 1) In severe HA the intron-22 inversion was the most common mutation (47/122, 38%). Missense mutations predominated in mild and moderate HA. Inhibitors were present in 44/318 patients, the majority of whom had 26/44 (59%) severe HA. 20/36 novel mutations (55%) were associated with severe HA, 12/36 (33%) with mild HA and 4/36 (11%) with a moderate HA. Novel mutations associated with non-severe phenotypes were mostly missense mutations (15/16); More diversity was seen in the novel mutations causing a severe HA with a fairly even distribution of mutations: missense (7/20), nonsense (4/20) and small deletions and insertions (8/20). One large deletion involving a 6.5kb region of exon 26, as well as one duplication of exons 7 to 9 - was seen in the severe group. In-silico analysis predicted that all novel severe HA mutations were likely to be pathogenic.Inhibitors were seen in 7 patients with novel mutations. Of the 36 novel mutations we described, 9/36 (25%) were seen in other family members - often female carriers. All 9 mutations caused a severe phenotype which is not unexpected given that the screening and testing of family members would be unlikely to take place in patients who have a mild phenotype and rarely require supportive medical care Conclusion: This study adds 36 novel mutations to the currently known FVIII haemophilic mutations. It also confirms that the frequency and correlative clinical severity of known genetic mutations in the Victorian HA cohort is similar to that described internationally. Disclosures No relevant conflicts of interest to declare.

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Novel Mutations in CLN5 of Chinese Patients With Neuronal Ceroid Lipofuscinosis

Journal of Child Neurology ◽

10.1177/0883073818789024 ◽

2018 ◽

Vol 33 (13) ◽

pp. 837-850 ◽

Cited By ~ 2

Author(s):

Lv Ge ◽

Han Yun Li ◽

Yuan Hai ◽

Liu Min ◽

Li Xing ◽

...

Keyword(s):

Age Of Onset ◽

Neuronal Ceroid Lipofuscinosis ◽

Hereditary Disease ◽

Chinese Patients ◽

Missense Mutations ◽

Novel Mutations ◽

Neuronal Protein ◽

Ceroid Lipofuscinosis ◽

Visual Problems ◽

Homozygous Mutations

Neuronal ceroid lipofuscinosis is a hereditary disease, and ceroid-lipofuscinosis neuronal protein 5 (CLN5) has been proved to be associated with neuronal ceroid lipofuscinosis. Here we report 3 patients from 2 families diagnosed with CLN5 neuronal ceroid lipofuscinosis. Whole genome sequencing of DNAs from 3 patients and their families revealed 3 novel homozygous mutations, including 1 deletion CLN5.c718 719delAT and 2 missense mutations c.1082T>C and c.623G>A. We reviewed 278 papers about neuronal ceroid lipofuscinosis resulting from CLN5 mutations and compared Chinese cases with 27 European and American cases. The overall age of onset of European and American patients occur mainly at 3 to 6 years (66%, 18/27), 100% (27/27) of patients had psychomotor regression, 99% (26/27) patients presented vision decline, and 70% (19/27) of patients suffered seizures. In China, the age of onset in 3 patients was 5 years, but for 1 patient it was at 17 months. Four Chinese patients presented psychomotor deterioration and seizures; only 1 had visual problems.

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