scholarly journals Familial autosomal recessive bestrophinopathy: identification of a novel variant in BEST1 gene and the specific metabolomic profile

2019 ◽  
Author(s):  
Panpan Ye ◽  
Jia Xu ◽  
Yueqiu Luo ◽  
Zhitao Su ◽  
ke yao
Keyword(s):  
Missense Mutation ◽  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Family Members ◽  
Subretinal Fluid ◽  
Retinal Disease ◽  
Angle Closure ◽  
Chinese Family ◽  
Disease Genes ◽  
Metabolomic Profile

Abstract BackgroundAutosomal recessive bestrophinopathy (ARB) is a retinal degenerative disorder caused by BEST1 mutations with autosomal recessive inheritance. We aim to map a comprehensive genomic and metabolomic profile of a consanguineous Chinese family with ARB.MethodsOphthalmic examinations were performed on the affected patients with ARB. The proband was screened for potential causative mutations in a panel with 256 known retinal disease genes by using target capture sequencing. The related mutation was further validated and segregated in the family members by Sanger sequencing. In silico prediction tools were used for pathogenicity assessment. A UHPLC-MS/MS metabolomic analysis was performed to explore the disease-associated metabolic feature.ResultsThe affected patients from this family were characterized by low vision, the presence of subretinal fluid, macular edema, and hyperopia with coincidental angle closure. DNA sequencing identified a novel missense mutation in the BEST1 gene c.646G>A (p.Val216Ile) of the proband. Sanger sequencing further confirmed the mutation. The missense mutation was co-segregation across the pedigree and predicted to be deleterious by SIFT (0.017). The blood metabolic profiles were highly similar among all family members probably because of the same lifestyle, habitat and genomic background. However, ARB patients presented a significant deregulation of metabolites, such as citric acid, L-Threonic acid, and eicosapentaenoic acid.ConclusionsWe identified a novel disease-associated variant in the BEST1 gene as well as a disease-specific metabolic feature in familial ARB. Our findings helped improve the understanding of ARB mechanisms.

scholarly journals Familial autosomal recessive bestrophinopathy: identification of a novel variant in BEST1 gene and the specific metabolomic profile

2020 ◽  
Author(s):  
Panpan Ye ◽  
Jia Xu ◽  
Yueqiu Luo ◽  
Zhitao Su ◽  
ke yao
Keyword(s):  
Missense Mutation ◽  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Family Members ◽  
Subretinal Fluid ◽  
Angle Closure ◽  
Chinese Family ◽  
Metabolomic Profile ◽  
Metabolic Feature ◽  
Autosomal Recessive Bestrophinopathy

Abstract Background Autosomal recessive bestrophinopathy (ARB) is a retinal degenerative disorder caused by BEST1 mutations with autosomal recessive inheritance. We aim to map a comprehensive genomic and metabolomic profile of a consanguineous Chinese family with ARB. Methods Ophthalmic examinations were performed on the affected patients with ARB. The proband was screened for potential causative mutations in a panel with 256 known retinal disease genes by using target capture sequencing. The related mutation was further validated and segregated in the family members by Sanger sequencing. In silico prediction tools were used for pathogenicity assessment. A UHPLC-MS/MS metabolomic analysis was performed to explore the disease-associated metabolic feature. Results The affected patients from this family were characterized by low vision, the presence of subretinal fluid, macular edema, and hyperopia with coincidental angle closure. DNA sequencing identified a novel missense mutation in the BEST1 gene c.646G>A (p.Val216Ile) of the proband. Sanger sequencing further confirmed the mutation. The missense mutation was co-segregation across the pedigree and predicted to be deleterious by SIFT (0.017). The blood metabolic profiles were highly similar among all family members probably because of the same lifestyle, habitat and genomic background. However, ARB patients presented a significant deregulation of metabolites, such as citric acid, L-Threonic acid, and eicosapentaenoic acid. Conclusions We identified a novel disease-associated variant in the BEST1 gene as well as a disease-specific metabolic feature in familial ARB . Our findings helped improve the understanding of ARB mechanisms.

scholarly journals Familial autosomal recessive bestrophinopathy: identification of a novel variant in BEST1 gene and the specific metabolomic profile

2020 ◽  
Author(s):  
Panpan Ye ◽  
Jia Xu ◽  
Yueqiu Luo ◽  
Zhitao Su ◽  
ke yao
Keyword(s):  
Missense Mutation ◽  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Family Members ◽  
Subretinal Fluid ◽  
Angle Closure ◽  
Chinese Family ◽  
Metabolomic Profile ◽  
Metabolic Feature ◽  
Autosomal Recessive Bestrophinopathy

Abstract Background Autosomal recessive bestrophinopathy (ARB) is a retinal degenerative disorder caused by BEST1 mutations with autosomal recessive inheritance. We aim to map a comprehensive genomic and metabolomic profile of a consanguineous Chinese family with ARB. Methods Ophthalmic examinations were performed on the affected patients with ARB. The proband was screened for potential causative mutations in a panel with 256 known retinal disease genes by using target capture sequencing. The related mutation was further validated and segregated in the family members by Sanger sequencing. In silico prediction tools were used for pathogenicity assessment. A UHPLC-MS/MS metabolomic analysis was performed to explore the disease-associated metabolic feature. Results The affected patients from this family were characterized by low vision, the presence of subretinal fluid, macular edema, and hyperopia with coincidental angle closure. DNA sequencing identified a novel missense mutation in the BEST1 gene c.646G>A (p.Val216Ile) of the proband. Sanger sequencing further confirmed the mutation. The missense mutation was co-segregation across the pedigree and predicted to be deleterious by SIFT (0.017). The blood metabolic profiles were highly similar among all family members probably because of the same lifestyle, habitat and genomic background. However, ARB patients presented a significant deregulation of metabolites, such as citric acid, L-Threonic acid, and eicosapentaenoic acid. Conclusions We identified a novel disease-associated variant in the BEST1 gene as well as a disease-specific metabolic feature in familial ARB . Our findings helped improve the understanding of ARB mechanisms.

scholarly journals Familial autosomal recessive bestrophinopathy: identification of a novel variant in BEST1 gene and the specific metabolomic profile

2020 ◽  
Author(s):  
Panpan Ye ◽  
Jia Xu ◽  
Yueqiu Luo ◽  
Zhitao Su ◽  
ke yao
Keyword(s):  
Missense Mutation ◽  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Family Members ◽  
Subretinal Fluid ◽  
Angle Closure ◽  
Chinese Family ◽  
Metabolomic Profile ◽  
Metabolic Feature ◽  
Autosomal Recessive Bestrophinopathy

Abstract Background Autosomal recessive bestrophinopathy (ARB) is a retinal degenerative disorder caused by BEST1 mutations with autosomal recessive inheritance. We aim to map a comprehensive genomic and metabolomic profile of a consanguineous Chinese family with ARB. Methods Ophthalmic examinations were performed on the affected patients with ARB. The proband was screened for potential causative mutations in a panel with 256 known retinal disease genes by using target capture sequencing. The related mutation was further validated and segregated in the family members by Sanger sequencing. In silico prediction tools were used for pathogenicity assessment. A UHPLC-MS/MS metabolomic analysis was performed to explore the disease-associated metabolic feature. Results The affected patients from this family were characterized by low vision, the presence of subretinal fluid, macular edema, and hyperopia with coincidental angle closure. DNA sequencing identified a novel missense mutation in the BEST1 gene c.646G>A (p.Val216Ile) of the proband. Sanger sequencing further confirmed the mutation. The missense mutation was co-segregation across the pedigree and predicted to be deleterious by SIFT (0.017). The blood metabolic profiles were highly similar among all family members probably because of the same lifestyle, habitat and genomic background. However, ARB patients presented a significant deregulation of metabolites, such as citric acid, L-Threonic acid, and eicosapentaenoic acid. Conclusions We identified a novel disease-associated variant in the BEST1 gene as well as a disease-specific metabolic feature in familial ARB . Our findings helped improve the understanding of ARB mechanisms.

scholarly journals Familial autosomal recessive bestrophinopathy: identification of a novel variant in BEST1 gene and the specific metabolomic profile

2019 ◽  
Author(s):  
Panpan Ye ◽  
Jia Xu ◽  
Yueqiu Luo ◽  
Zhitao Su ◽  
Ke Yao
Keyword(s):  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Low Vision ◽  
Subretinal Fluid ◽  
Retinal Disease ◽  
Autosomal Recessive Inheritance ◽  
Angle Closure ◽  
Chinese Family ◽  
Disease Genes ◽  
Autosomal Recessive Bestrophinopathy

Abstract Background Autosomal recessive bestrophinopathy (ARB) is a retinal degenerative disorder caused by BEST1 mutations with autosomal recessive inheritance. We aim to map a comprehensive genomic and metabolic profile of a consanguineous Chinese family with ARB.Methods Ophthalmic examinations were performed on affected patients with ARB. Target capture sequencing was performed to screen causative mutations in 256 known retinal disease genes and Sanger sequencing were used for verification. A UHPLC-MS/MS metabolomic analysis was performed to explore the disease-associated metabolic feature.Results Affected patients from this family are characterized by low vision, the presence of subretinal fluid, macular edema, and hyperopia with coincidental angle closure. DNA sequencing identified a novel missense mutation in BEST1 gene (chr11:61725867G>A) of the proband. Sanger sequencing further confirmed the mutation. The blood metabolic profiles were very similar among all family members probably due to the same life style, habitats and genomic background. However, ARB patients presented significant deregulation of metabolites such as Citric acid, L-Threonic acid, Eicosapentaenoic acid.Conclusions We identified a novel disease-associated variant in BEST1 gene as well as the disease-specific metabolic feature in familial ARB. The findings improved the understanding of mechanisms of ARB and provided a potential therapeutic strategy with application of metabolomics.

scholarly journals Familial autosomal recessive bestrophinopathy: identification of a novel variant in BEST1 gene and the specific metabolomic profile

2019 ◽  
Author(s):  
Panpan Ye ◽  
Jia Xu ◽  
Yueqiu Luo ◽  
Zhitao Su ◽  
ke yao
Keyword(s):  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Low Vision ◽  
Subretinal Fluid ◽  
Retinal Disease ◽  
Autosomal Recessive Inheritance ◽  
Angle Closure ◽  
Chinese Family ◽  
Disease Genes ◽  
Target Capture

Abstract BackgroundAutosomal recessive bestrophinopathy (ARB) is a retinal degenerative disorder caused by BEST1 mutations with autosomal recessive inheritance. We aim to map a comprehensive genomic and metabolic profile of a consanguineous Chinese family with ARB.MethodsOphthalmic examinations were performed on affected patients with ARB. Target capture sequencing was performed to screen causative mutations in 256 known retinal disease genes and Sanger sequencing were used for verification. A UHPLC-MS/MS metabolomic analysis was performed to explore the disease-associated metabolic feature.ResultsAffected patients from this family were characterized by low vision, the presence of subretinal fluid, macular edema, and hyperopia with coincidental angle closure. DNA sequencing identified a novel missense mutation in BEST1 gene (chr11:61725867G>A) of the proband. Sanger sequencing further confirmed the mutation. The blood metabolic profiles were highly similar among all family members probably due to the same life style, habitats and genomic background. However, ARB patients presented significant deregulation of metabolites such as Citric acid, L-Threonic acid, Eicosapentaenoic acid.Conclusions We identified a novel disease-associated variant in BEST1 gene as well as a disease-specific metabolic feature in familial ARB. The findings improved the understanding of mechanisms of ARB and provided a potential therapeutic strategy with application of metabolomics.

scholarly journals PRPF3-Associated Autosomal Dominant Retinitis Pigmentosa and CYP4V2-Associated Bietti’s Crystalline Corneoretinal Dystrophy Coexist in a Multigenerational Chinese Family

2017 ◽  
Vol 2017 ◽  
pp. 1-10
Author(s):  
Xiaohong Meng ◽  
Qiyou Li ◽  
Hong Guo ◽  
Haiwei Xu ◽  
Shiying Li ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Clinical Features ◽  
Sanger Sequencing ◽  
Mutation Screening ◽  
Retinal Dystrophy ◽  
Family Members ◽  
Large Family ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Genetic Characteristics

Purpose. To characterize the clinical and molecular genetic characteristics of a large, multigenerational Chinese family showing different phenotypes. Methods. A pedigree consisted of 56 individuals in 5 generations was recruited. Comprehensive ophthalmic examinations were performed in 16 family members affected. Mutation screening of CYP4V2 was performed by Sanger sequencing. Next-generation sequencing (NGS) was performed to capture and sequence all exons of 47 known retinal dystrophy-associated genes in two affected family members who had no mutations in CYP4V2. The detected variants in NGS were validated by Sanger sequencing in the family members. Results. Two compound heterozygous CYP4V2 mutations (c.802-8_810del17insGC and c.992A>C) were detected in the proband who presented typical clinical features of BCD. One missense mutation (c.1482C>T, p.T494M) in the PRPF3 gene was detected in 9 out of 22 affected family members who manifested classical clinical features of RP. Conclusions. Our results showed that two compound heterozygous CYP4V2 mutations caused BCD, and one missense mutation in PRPF3 was responsible for adRP in this large family. This study suggests that accurate phenotypic diagnosis, molecular diagnosis, and genetic counseling are necessary for patients with hereditary retinal degeneration in some large mutigenerational family.

scholarly journals Novel SOX2 Mutation in Autosomal Dominant Cataract-Microcornea Syndrome

2021 ◽  
Author(s):  
Zhi-Bo Lin ◽  
Jin Li ◽  
Hai-Sen Sun ◽  
A-Yong Yu ◽  
Shi-Hao Chen ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Family Members ◽  
High Mobility ◽  
Chinese Family ◽  
Whole Exome

Abstract Background: Congenital cataract-microcornea syndrome (CCMC) is characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. Although several causative genes have been reported in patients with CCMC, the genetic etiology of CCMC is yet to be clearly understood. Purpose: To unravel the genetic cause of autosomal dominant family with CCMC.Methods: All patients and available family members underwent a comprehensive ophthalmologic clinical examination in the hospital by expert ophthalmologists and carried out to clinically diagnosis. All the patients were screened by whole-exome sequencing and then validated using co-segregation by Sanger sequencing. Results: Four CCMC patients from a Chinese family, and five unaffected family members were enrolled in this study. Using whole-exome sequencing, missense mutation c.295G>T (p.a99s, NM_003106.4) in the SOX2 gene was identified and validated by segregation analysis. In addition, this missense mutation was predicted to be damaging by multiple predictive tools. Variant p.Ala99Ser was located in a conservation high mobility group (HMG)-box domain in SOX2 protein, with a potential pathogenic impact of p.Ala99Ser on protein level.Conclusions: A novel missense mutation (c.295G>T, p.Ala99Ser) in the SOX2 gene was found in this Han Chinese family with congenital cataract and microcornea. Our study firstly determined that mutations in SOX2 were associated with CCMC, warranting further investigations on the pathogenesis of this disorder. This result expands the mutation spectrum of SOX2 and provides useful information to study the molecular pathogenesis of CCMC.

scholarly journals Novel missense mutation of SASH1 in a Chinese family with dyschromatosis universalis hereditaria

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lu Cao ◽  
Ruixue Zhang ◽  
Liang Yong ◽  
Shirui Chen ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Sequence Alignment ◽  
Multiple Sequence Alignment ◽  
Molecular Genetic ◽  
Family Members ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Mendelian Inheritance ◽  
Chinese Family ◽  
Multiple Sequence

Abstract Background Dyschromatosis universalis hereditaria (DUH) is a pigmentary dermatosis characterized by generalized mottled macules with hypopigmention and hyperpigmention. ABCB6 and SASH1 are recently reported pathogenic genes related to DUH, and the aim of this study was to identify the causative mutations in a Chinese family with DUH. Methods Sanger sequencing was performed to investigate the clinical manifestation and molecular genetic basis of these familial cases of DUH, bioinformatics tools and multiple sequence alignment were used to analyse the pathogenicity of mutations. Results A novel missense mutation, c.1529G>A, in the SASH1 gene was identified, and this mutation was not found in the National Center for Biotechnology Information Database of Short Genetic Variation, Online Mendelian Inheritance in Man, ClinVar, or 1000 Genomes Project databases. All in silico predictors suggested that the observed substitution mutation was deleterious. Furthermore, multiple sequence alignment of SASH1 revealed that the p.S510N mutation was highly conserved during evolution. In addition, we reviewed the previously reported DUH-related gene mutations in SASH1 and ABCB6. Conclusion Although the affected family members had identical mutations, differences in the clinical manifestations of these family members were observed, which reveals the complexity of the phenotype-influencing factors in DUH. Our findings reveal the mutation responsible for DUH in this family and broaden the mutational spectrum of the SASH1 gene.

Probable Novel PSEN1 Gln222Leu Mutation in a Chinese Family with Early-Onset Alzheimer's Disease

2019 ◽  
Vol 16 (8) ◽  
pp. 764-769 ◽  
Author(s):  
Huayuan Wang ◽  
Ruihua Sun ◽  
Yingying Shi ◽  
Mingrong Xia ◽  
Jing Zhao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Missense Mutation ◽  
Early Onset ◽  
Sanger Sequencing ◽  
Pathogenic Mutation ◽  
Presenilin 1 ◽  
Chinese Family ◽  
Whole Exome ◽  
Early Onset Alzheimer’S Disease

Background: The rate of occurrence of Alzheimer’s disease is increasing around the world. However, there is still no significant breakthrough in the study of its etiology and pathogenesis. Objective: To screen Alzheimer's disease pathogenic genes, which may be conducive to the elucidation of the pathogenic mechanisms of Alzheimer's disease And predict the pathogenicity by various computer software. Method: Clinical and neuroimaging examination, Whole Exome Sequencing, and Sanger sequencing were performed in the proband. Mutation sites were verified in 158 subjects. Results: We reported a proband carrying a probably novel pathogenic mutation, which clinically manifests as progressive memory loss, visual-spatial disorders, apraxia, psychobehavioral disorders, and temperamental and personality changes. Whole Exome Sequencing detected a novel missense mutation at codon 222 (Q222L), which is a heterozygous A to T point mutation at position 665 (c.665A>T) in exon 5 of the presenilin 1 leading to a glutamine-to-leucine substitution. The mutation was also identified by Sanger sequencing in one family member; nevertheless, it was not detected in the other 7 unaffected family members, 50 sporadic Alzheimer's disease patients and 100 control subjects. Conclusion: A novel mutation in exon 5 of the presenilin 1 gene (Gln222Leu) in a Chinese family with early-onset Alzheimer’s disease has been reported, besides， it was predicted that the missense mutation was probably a novel pathogenic mutation that was reported for the first time in a Chinese family with early-onset Alzheimer’s disease.

scholarly journals A Missense Mutation in OPA1 Causes Dominant Optic Atrophy in a Chinese Family

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Shaoyi Mei ◽  
Xiaosheng Huang ◽  
Lin Cheng ◽  
Shiming Peng ◽  
Tianhui Zhu ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Optic Atrophy ◽  
Clinical Characteristics ◽  
Hand Movement ◽  
Family Members ◽  
Clinical Manifestations ◽  
Chinese Family ◽  
Variable Degree ◽  
Dominant Optic Atrophy ◽  
The Family

Background. To investigate the genetic causes and clinical characteristics of dominant optic atrophy (DOA) in a Chinese family. Methods. A 5-generation pedigree of 35 family members including 12 individuals affected with DOA was recruited from Shenzhen Eye Hospital, China. Four affected family members and one unaffected family member were selected for whole exome sequencing. Sanger sequencing was used to confirm and screen the identified mutation in 18 members of the family. The disease-causing mutation was identified by bioinformatics analysis and confirmed by segregation analysis. The clinical characteristics of the family members were analyzed. Results. A heterozygous missense mutation (c.1313A>G, p.D438G) in optic atrophy 1 (OPA1) was identified in 10 individuals affected with DOA in this family. None of the unaffected family members had the mutation. Patients in this family had vision loss since they were children or adolescence. The visual acuity decreased progressively to hand movement, except for one patient (IV-12) who had relatively good vision of 20/30 and 20/28. The fundus typically manifested as optic disc pallor. The visual fields, optical coherence tomography, and visual evoked potential suggested variable degree of abnormality in patients. Patients who had a history of cigarette smoking and alcohol drinking had more severe clinical manifestations. Conclusions. Our results suggest that the p.D438G mutation in OPA1 causes optic atrophy in this family. The patients who carried the mutation demonstrated heterogeneous clinical manifestations in this family. This is the first report on the c.1313A>G (p.D438G) mutation of OPA1 in a Chinese family affected with DOA.

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