scholarly journals Novel Missense Mutations in BEST1 Are Associated with Bestrophinopathies in Lebanese Patients

Genes ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 151 ◽  
Author(s):  
Lama Jaffal ◽  
Wissam Joumaa ◽  
Alexandre Assi ◽  
Charles Helou ◽  
Christel Condroyer ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Subretinal Fluid ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Autosomal Recessive Bestrophinopathy ◽  
Homozygous Mutations ◽  
Flanking Regions ◽  
Reduced Light ◽  
Exon 10

To identify Bestrophin 1 (BEST1) causative mutations in six Lebanese patients from three families, of whom four had a presumed clinical diagnosis of autosomal recessive bestrophinopathy (ARB) and two showed a phenotype with a single vitelliform lesion, patients were subjected to standard ophthalmic examinations. In addition, BEST1 exons and their flanking regions were amplified and sequenced by Sanger sequencing. Co-segregation and detailed bio-informatic analyses were performed. Clinical examination results were consistent with ARB diagnosis for all index patients showing multifocal vitelliform lesions and a markedly reduced light peak in the electrooculogram, including the two patients with a single vitelliform lesion. In all cases, most likely disease-causing BEST1 mutations co-segregated with the phenotype. The ARB cases showed homozygous missense variants (M1, c.209A>G, p.(Asp70Gly) in exon 3, M2, c.1403C>T; p.(Pro468Leu) in exon 10 and M3, c.830C>T, p.(Thr277Met) in exon 7), while the two patients with a single vitelliform lesion were compound heterozygous for M1 and M2. To our knowledge, this is the first study describing mutations in Lebanese patients with bestrophinopathy, where novel biallelic BEST1 mutations associated with two phenotypes were identified. Homozygous mutations were associated with multifocal lesions, subretinal fluid, and intraretinal cysts, whereas compound heterozygous ones were responsible for a single macular vitelliform lesion.

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 Bilateral Choroidal Neovascularization and Chorioretinal Anastomosis in Autosomal Recessive Bestrophinopathy

2019 ◽  
Vol 4 (1) ◽  
pp. 69-74
Author(s):  
Youning Zhang ◽  
Jennifer Danesh ◽  
Kyle M. Green ◽  
Ryan J. Schmidt ◽  
Jaclyn Biegel ◽  
...  
Keyword(s):  
Case Report ◽  
Choroidal Neovascularization ◽  
Autosomal Recessive ◽  
Subretinal Fluid ◽  
Compound Heterozygous ◽  
Factor Therapy ◽  
Chorioretinal Anastomosis ◽  
Autosomal Recessive Bestrophinopathy ◽  
Growth Factor Therapy ◽  
Endothelial Growth Factor

Purpose: This case report discusses a case of bilateral chorioretinal anastomoses in autosomal recessive bestrophinopathy (ARB) unresponsive to antivascular endothelial growth factor therapy and its associated optical coherence tomography angiography (OCTA) findings. Methods: An observational case report is presented. Results: An 8-year-old girl initially presented at age 2 years with multifocal midperipheral yellow subretinal deposits with intraretinal and subretinal fluid. She was treated with intravitreal injections of bevacizumab in both eyes with minimal response. OCTA revealed the presence of choroidal neovascularization and chorioretinal anastomoses. Molecular diagnosis of ARB was achieved with the identification of compound heterozygous mutations in BEST1, including a silent exonic splicing mutation. Conclusions: Subretinal or intraretinal fluid in ARB may be exacerbated by the presence of chorioretinal anastomosis detected on OCTA. Silent exonic mutations that cause no amino acid change can be overlooked but are pathogenic in ARB.

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

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.

Hereditary vitamin D-resistant rickets in Lebanese patients: the p.R391S and p.H397P variants have different phenotypes

2017 ◽  
Vol 30 (4) ◽  
Author(s):  
Rabih Andary ◽  
Abdul-Karim El-Hage-Sleiman ◽  
Theresa Farhat ◽  
Sami Sanjad ◽  
Georges Nemer
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Normal Phenotype ◽  
Vitamin D Resistant Rickets ◽  
Exon 9 ◽  
Homozygous Mutations ◽  
Resistant Rickets

Abstract:Background:Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disorder caused by mutations in the vitamin D receptor (Methods:We examined four patients with HVDRR from three unrelated Lebanese families. All parents were consanguineous with normal phenotype. We used Sanger sequencing to identify mutations in the coding exons ofResults:Two homozygous mutations (p.R391S and p.H397P), both in exon 9 of theConclusions:This is the first report of

scholarly journals Acute recurrent rhabdomyolysis in a Chinese boy associated with a novel compound heterozygous LPIN1 variant: a case report

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ke Tong ◽  
Geng-Sheng Yu
Keyword(s):  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Missense Variant ◽  
Serum Creatine Kinase ◽  
Accurate Diagnosis ◽  
Strenuous Exercise ◽  
Compound Heterozygous ◽  
Case Presentation ◽  
Heterozygous Variant ◽  
Recurrent Rhabdomyolysis

Abstract Background LPIN1-related acute recurrent rhabdomyolysis (RM), first reported in 2008, is an autosomal recessive inherited metabolic disease. In recent years, LPIN1 gene variants have been identified as one of the main causes of severe RM in children in Western countries. The disease is extremely rare in China, and we report a case of acute recurrent RM caused by a novel compound heterozygous LPIN1 variant. Case presentation A 15-year-old Chinese boy presented with myalgia after strenuous exercise, accompanied by transient increases in serum creatine kinase and myoglobin and persistent hyperuricaemia and hyperbilirubinaemia. Genetic analysis using high-throughput genomic sequencing and Sanger sequencing revealed that there was a compound heterozygous variant in the LPIN1 gene of the proband: the paternal c.2047A > G(p.I683V) was an unreported missense variant, and the maternal c.2107_2108 insAGG(p.Q703delin sQE) was an unreported in-frame variant. Conclusions In children with RM, LPIN1 variants should always be considered in the differential diagnosis. The clinical features of our case are atypical, which highlights the importance of an accurate diagnosis by genetic testing. If detected early, the condition may be controlled, and the prognosis may be improved.

Compound Heterozygosity for Two Novel Missense Mutations in the Prothrombin Gene in a Patient with a Severe Bleeding Tendency

1997 ◽  
Vol 77 (04) ◽  
pp. 610-615 ◽  
Author(s):  
S R Poort ◽  
R Landolfi ◽  
R M Bertina
Keyword(s):  
Catalytic Domain ◽  
Point Mutations ◽  
Severe Bleeding ◽  
Bleeding Tendency ◽  
Missense Mutations ◽  
Sequence Variations ◽  
Pcr Products ◽  
Prothrombin Gene ◽  
Flanking Regions ◽  
Exon 10

SummaryThe abnormal prothrombin gene of an Italian patient with a severe bleeding tendency and hypoprothrombinemia was selected for study and compared with the prothrombin genes of healthy controls. All the coding and their flanking regions and the 5ʹ- and 3ʹ-UT regions of the prothrombin gene were screened by analyzing the nucleotide sequence of the corresponding PCR products. The patient was found to be heterozygous for two novel point mutations: one at nucleotide 4251 in exon 6, which changes the codon for cysteine-138 (TGC) in the kringle 1 domain to that for tyrosine (TAC), and one at nucleotide 8812 in exon 10, which results in the replacement of tryptophan-357 (TGG) by cysteine (TGT) in the catalytic domain. Her mother was heterozygous for the Cys-138 Tyr mutation and her father heterozygous for the Trp-357 Cys mutation. Several other sequence variations were identified in the prothrombin genes from control individuals. Only the variations at nucleotide 4203 and 10253 could be established as polymorphisms.

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.

Functional Characterization of Bestrophin-1 Missense Mutations Associated with Autosomal Recessive Bestrophinopathy

2011 ◽  
Vol 52 (6) ◽  
pp. 3730 ◽  
Author(s):  
Alice E. Davidson ◽  
Ian D. Millar ◽  
Rosemary Burgess-Mullan ◽  
Geoffrey J. Maher ◽  
Jill E. Urquhart ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Functional Characterization ◽  
Missense Mutations ◽  
Autosomal Recessive Bestrophinopathy
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