10 results on '"De Roach JN"'
Search Results
2. Clinical Evidence for the Importance of the Wild-Type PRPF31 Allele in the Phenotypic Expression of RP11.
- Author
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Roshandel D, Thompson JA, Heath Jeffery RC, Zhang D, Lamey TM, McLaren TL, De Roach JN, McLenachan S, Mackey DA, and Chen FK
- Subjects
- Adolescent, Adult, Aged, Female, Humans, Male, Middle Aged, Mutation, Pedigree, Retinitis Pigmentosa pathology, Alleles, Eye Proteins genetics, Phenotype, Retinitis Pigmentosa genetics
- Abstract
PRPF31 -associated retinopathy (RP11) is a common form of autosomal dominant retinitis pigmentosa (adRP) that exhibits wide variation in phenotype ranging from non-penetrance to early-onset RP. Herein, we report inter-familial and intra-familial variation in the natural history of RP11 using multimodal imaging and microperimetry. Patients were recruited prospectively. The age of symptom onset, best-corrected visual acuity, microperimetry mean sensitivity (MS), residual ellipsoid zone span and hyperautofluorescent ring area were recorded. Genotyping was performed using targeted next-generation and Sanger sequencing and copy number variant analysis. PRPF31 mutations were found in 14 individuals from seven unrelated families. Four disease patterns were observed: (A) childhood onset with rapid progression ( N = 4), (B) adult-onset with rapid progression ( N = 4), (C) adult-onset with slow progression ( N = 4) and (D) non-penetrance ( N = 2). Four different patterns were observed in a family harbouring c.267del; patterns B, C and D were observed in a family with c.772_773delins16 and patterns A, B and C were observed in 3 unrelated individuals with large deletions. Our findings suggest that the RP11 phenotype may be related to the wild-type PRPF31 allele rather than the type of mutation. Further studies that correlate in vitro wild-type PRPF31 allele expression level with the disease patterns are required to investigate this association.
- Published
- 2021
- Full Text
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3. Multimodal Retinal Imaging and Microperimetry Reveal a Novel Phenotype and Potential Trial End Points in CRB1-Associated Retinopathies.
- Author
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Roshandel D, Thompson JA, Heath Jeffery RC, Sampson DM, Chelva E, McLaren TL, Lamey TM, De Roach JN, Durkin SR, and Chen FK
- Subjects
- Humans, Membrane Proteins genetics, Nerve Tissue Proteins genetics, Phenotype, Retina, Visual Field Tests, Eye Proteins genetics, Retinitis Pigmentosa diagnosis
- Abstract
Purpose: Biallelic crumbs cell polarity complex component 1 (CRB1) mutations can present as Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), or cystic maculopathy. This study reports a novel phenotype of asymptomatic fenestrated slit maculopathy (AFSM) and examines macular volume profile and microperimetry as clinical trial end points in CRB1-associated retinopathies., Methods: Twelve patients from nine families with CRB1 mutation were recruited. Ultra-widefield (UWF) color fundus photography and autofluorescence (AF), spectral-domain optical coherence tomography (SD-OCT), microperimetry, and adaptive optics (AO) imaging were performed. Macular volume profiles were compared with age-matched healthy controls. Genotyping was performed using APEX genotyping microarrays, targeted next-generation sequencing, and Sanger sequencing., Results: We identified one patient with LCA, five patients with RP, and four patients with macular dystrophy (MD) with biallelic CRB1 mutations. Two siblings with compound heterozygote genotype (c.[2843G>A]; [498_506del]) had AFSM characterized by localized outer retinal disruption on SD-OCT and parafoveal cone loss on AO imaging despite normal fundus appearance, visual acuity, and foveal sensitivity. UWF AF demonstrated preserved para-arteriolar retinal pigment epithelium (PPRPE) in all patients with RP. Microperimetry documented preserved central retinal function in six patients. The ratio of perifoveal-to-foveal retinal volume was greater than controls in 89% (8/9) of patients with RP or MD, whereas central subfield and total macular volume were outside normal limits in 67% (6/9)., Conclusions: AO imaging was helpful in detecting parafoveal cone loss in asymptomatic patients. Macular volume profile and microperimetry parameters may have utility as CRB1 trials end points., Translational Relevance: Macular volume and sensitivity can be used as structural and functional end points for trials on CRB1-associated RP and MD.
- Published
- 2021
- Full Text
- View/download PDF
4. Exploring microperimetry and autofluorescence endpoints for monitoring disease progression in PRPF31 -associated retinopathy.
- Author
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Roshandel D, Thompson JA, Charng J, Zhang D, Chelva E, Arunachalam S, Attia MS, Lamey TM, McLaren TL, De Roach JN, Mackey DA, Wilton SD, Fletcher S, McLenachan S, and Chen FK
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Disease Progression, Female, Heterozygote, Humans, Male, Middle Aged, Pedigree, Retinitis Pigmentosa diagnostic imaging, Retinitis Pigmentosa genetics, Visual Acuity, Visual Field Tests, Young Adult, Eye Proteins genetics, Mutation, Optical Imaging methods, Phenotype, Retinitis Pigmentosa pathology, Tomography, Optical Coherence methods
- Abstract
Background: Mutations in the splicing factor pre-messenger RNA processing factor 31 ( PRPF31 ) gene cause autosomal dominant retinitis pigmentosa 11 (RP11) through a haplo-insufficiency mechanism. We describe the phenotype and progression of microperimetry and autofluorescence endpoints in an Indigenous Australian RP11 family., Patients and Methods: Ophthalmic examination, optical coherence tomography, fundus autofluorescence and microperimetry were performed at baseline and every 6-12 months. Baseline and annual change in best-corrected visual acuity (BCVA), microperimetry mean sensitivity (MS) and number of scotoma loci, residual ellipsoid zone (EZ) span and hyperautofluorescent ring (HAR) area were reported. Next-generation and Sanger sequencing were performed in available members., Results: 12 affected members from three generations were examined. Mean (SD, range) age at onset of symptoms was 11 (4.5, 4-19) years. MS declined steadily from the third decade and EZ span and HAR area declined rapidly during the second decade. Serial microperimetry showed negligible change in MS over 2-3 years. However, mean EZ span, near-infrared and short-wavelength HAR area reduction was 203 (6.4%) µm/year, 1.8 (8.7%) mm
2 /year and 1.1 (8.6%) mm2 /year, respectively. Genetic testing was performed on 11 affected and 10 asymptomatic members and PRPF31 c.1205 C > A (p.Ser402Ter) mutation was detected in all affected and two asymptomatic members (non-penetrant carriers)., Conclusions: Our findings suggest that in the studied cohort, the optimal window for therapeutic intervention is the second decade of life and residual EZ span and HAR area can be considered as efficacy outcome measures. Further studies on larger samples with different PRPF31 mutations and longer follow-up duration are recommended.- Published
- 2021
- Full Text
- View/download PDF
5. Progressive sector retinitis pigmentosa due to c.440G>T mutation in SAG in an Australian family.
- Author
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Pappalardo J, Heath Jeffery RC, Thompson JA, Charng J, Chelva ES, Constable IJ, McLaren TL, Lamey TM, De Roach JN, and Chen FK
- Subjects
- Adult, Aged, Australia, Disease Progression, Female, Humans, Male, Middle Aged, Pedigree, Retinitis Pigmentosa etiology, Retinitis Pigmentosa metabolism, Visual Fields, Calcium-Binding Proteins genetics, DNA-Binding Proteins genetics, Mutation, Retinitis Pigmentosa pathology, Tumor Suppressor Proteins genetics
- Abstract
Background: Heterozygous c.440 G > T mutation in the S-antigen visual arrestin (SAG) gene has been described as a cause of autosomal dominant retinitis pigmentosa (adRP) in a series of patients of Hispanic origin. This study presents the early and late clinical features and disease progression rates in an Australian family with SAG adRP., Materials and Methods: An observational case series of four family members with adRP. They were examined clinically, with multi-modal retinal imaging and electroretinography (ERG) to ascertain phenotype. Disease progression rate was measured using optical coherence tomography (OCT) and fundus autofluorescence (FAF). A retinal dystrophy panel was used for the proband and cascade testing with targeted Sanger sequencing was conducted in other available family members., Results: The proband presented at 36 years of age with profoundly reduced full-field ERG responses despite a sector RP phenotype. This progressed to a classic RP pattern over several decades leaving a small residual island of central visual field. The horizontal span of the residual outer nuclear layer and the area of hyperautofluorescent ring contracted at a rate of 8-11% and 9-14% per year, respectively. DNA sequencing confirmed the segregation of SAG c.440 G > T mutation with disease., Conclusion: SAG adRP presents with a reduced full-field ERG response consistent with a rod-cone dystrophy in mid-life despite a sector RP phenotype. Centripetal progression of the disease into the macula can be tracked by OCT and FAF imaging.
- Published
- 2021
- Full Text
- View/download PDF
6. Generation of an induced pluripotent stem cell line from a patient with retinitis pigmentosa caused by RP1 mutation.
- Author
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Zhang X, Moon SY, Zhang D, Chen SC, Lamey T, Thompson JA, McLaren T, De Roach JN, McLenachan S, and Chen FK
- Subjects
- Aged, Cells, Cultured, Female, Fibroblasts metabolism, Humans, Induced Pluripotent Stem Cells metabolism, Kruppel-Like Factor 4, Phenotype, Retinitis Pigmentosa pathology, Cell Differentiation, Cellular Reprogramming, Fibroblasts pathology, Induced Pluripotent Stem Cells pathology, Microtubule-Associated Proteins genetics, Mutation, Retinitis Pigmentosa genetics
- Abstract
We report the generation of the iPSC line LEIi005-B from a patient with retinitis pigmentosa caused by a dominant nonsense mutation in the RP1 gene (c.2098G>T p.E700X). Reprogramming of dermal fibroblasts was performed using episomal plasmids containing OCT4, SOX2, KLF4, L-MYC, LIN28, mir302/367 microRNA and shRNA for p53 to establish the clonal iPSC line LEIi005-B. LEIi005-B expressed pluripotent stem cell markers, had a normal karyotype and differentiated into endoderm, mesoderm and ectoderm., (Copyright © 2019. Published by Elsevier B.V.)
- Published
- 2019
- Full Text
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7. Development of High-Throughput Clinical Testing of RPGR ORF15 Using a Large Inherited Retinal Dystrophy Cohort.
- Author
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Chiang JPW, Lamey TM, Wang NK, Duan J, Zhou W, McLaren TL, Thompson JA, Ruddle J, and De Roach JN
- Subjects
- Adult, Cohort Studies, DNA Mutational Analysis, Female, Genetic Diseases, X-Linked genetics, Humans, Male, Pedigree, Polymerase Chain Reaction, Reproducibility of Results, Retinitis Pigmentosa genetics, Sensitivity and Specificity, Eye Proteins genetics, Genetic Diseases, X-Linked diagnosis, High-Throughput Nucleotide Sequencing, Mutation, Open Reading Frames genetics, Retinitis Pigmentosa diagnosis
- Abstract
Purpose: Mutations in the ORF15 region of RPGR account for approximately half of all X-linked retinitis pigmentosa cases. However, a robust high-throughput method for the detection of ORF15 mutations has yet to be validated. We set out to develop the first clinically validated next-generation sequencing (NGS) method for the detection of mutations in this difficult-to-sequence region, including test accuracy and coverage data., Methods: As part of a blind-test, 145 research samples, previously tested by Sanger sequencing, and 81 clinical samples were evaluated using NGS of long-range PCR products fragmented with Illumina's Nextera library preparation kit (method 1), or with Centrillion's OneTube technology, supplemented with duplication analysis using an ORF15-specific in-silico array (method 2). DNA fragments were analyzed using Agilent's DNA 1000 assay, and sequencing was done on Illumina's MiSeq 2×150 or HiSeq2500 2×100. NextGENe by SoftGenetics was used for data analysis and variant calling., Results: The Nextera library preparation method produced 24 cases of discordance due to (in order of decreasing occurrence) false-negatives, incorrectly called variants, and a false-positive. Subsequent use of a new, OneTube NGS library preparation method, supplemented with duplication analyses, resolved discordance between Sanger and NGS data in all cases. This improvement in variant detection accuracy was largely attributed to improvement in random fragmentation offered by the enzymatic OneTube method, resulting in more complete coverage of the highly repetitive ORF15 region. Minimum coverage was roughly 320 reads for Nextera and 6800 reads for OneTube (normalized for total read counts)., Conclusions: This paper documents the first clinically validated NGS method for reliable, high-throughput sequencing of RPGR ORF15. Sensitivity and specificity of the new method were 100%, with the caveat of unclear zygosity calling for one large duplication case. These findings demonstrate a reliable and practical implementation for NGS-based diagnosis of RPGR ORF15 mutations. They also provide the foundation for targeted, high-coverage sequencing of any other repetitive regions within the genome.
- Published
- 2018
- Full Text
- View/download PDF
8. Establishment of an induced pluripotent stem cell line from a retinitis pigmentosa patient with compound heterozygous CRB1 mutation.
- Author
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Zhang X, Zhang D, Chen SC, Lamey T, Thompson JA, McLaren T, De Roach JN, Chen FK, and McLenachan S
- Subjects
- Cell Differentiation, Cell Line, Female, Humans, Kruppel-Like Factor 4, Middle Aged, Mutation, Eye Proteins metabolism, Induced Pluripotent Stem Cells metabolism, Membrane Proteins metabolism, Nerve Tissue Proteins metabolism, Retinitis Pigmentosa genetics
- Abstract
The human iPSC line LEIi006-A was generated from dermal fibroblasts from a patient with retinitis pigmentosa using episomal plasmids containing OCT4, SOX2, KLF4, L-MYC, LIN28, mir302/367 microRNA and shRNA for p53. The iPSC cells carry compound heterozygous mutations (c.1892A > G and c.2548G > A) in the CRB1 gene. LEIi006-A expressed pluripotent stem cell markers, had a normal karyotype and could be differentiated into endoderm, mesoderm and ectodermal lineages, as well as retinal organoids., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
9. Maternal uniparental isodisomy of chromosome 6 unmasks a novel variant in TULP1 in a patient with early onset retinal dystrophy.
- Author
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Souzeau E, Thompson JA, McLaren TL, De Roach JN, Barnett CP, Lamey TM, and Craig JE
- Subjects
- Chromosomes, Human, Pair 6 chemistry, Electroretinography, Female, Gene Expression, Homozygote, Humans, Leber Congenital Amaurosis diagnosis, Leber Congenital Amaurosis pathology, Maternal Inheritance, Mutation, Myopia diagnosis, Myopia pathology, Night Blindness diagnosis, Night Blindness pathology, Nystagmus, Congenital diagnosis, Nystagmus, Congenital pathology, Retinitis Pigmentosa diagnosis, Retinitis Pigmentosa pathology, Young Adult, Eye Proteins genetics, Leber Congenital Amaurosis genetics, Myopia genetics, Night Blindness genetics, Nystagmus, Congenital genetics, Retinitis Pigmentosa genetics, Uniparental Disomy
- Abstract
Purpose: Inherited retinal dystrophies are a clinically and genetically heterogeneous group of disorders. Molecular diagnosis has proven utility for affected individuals. In this study, we report an individual enrolled in the Australian Inherited Retinal Disease Registry and DNA Bank diagnosed with clinical features overlapping between Leber congenital amaurosis and retinitis pigmentosa., Methods: DNA from the proband was sequenced using a gene panel for inherited retinal disorders, and a single nucleotide polymorphism (SNP) array was conducted to detect the presence of deletions and uniparental disomy., Results: We identified a novel homozygous variant (c.524dupC, p.(Pro176ThrfsTer7)) in TULP1 resulting from maternal uniparental isodisomy of chromosome 6. The patient had clinical features consistent with biallelic pathogenic variants in TULP1 , including congenital nystagmus, night blindness, non-recordable electroretinogram, mild myopia, and mild peripheral pigmentary changes in the fundus., Conclusions: This is the first report of uniparental disomy 6 and a homozygous variant in TULP1 associated with a rod-cone dystrophy. Molecular diagnosis of inherited retinal dystrophies is essential to inform the mode of transmission and clinical management, and to identify potential candidates for future gene-specific therapies.
- Published
- 2018
10. Application of a high-throughput genotyping method for loci exclusion in non-consanguineous Australian pedigrees with autosomal recessive retinitis pigmentosa.
- Author
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Paterson RL, De Roach JN, McLaren TL, Hewitt AW, Hoffmann L, and Lamey TM
- Subjects
- Australia, Case-Control Studies, Female, Genes, Recessive, Genetic Linkage, Haplotypes, Humans, Male, Multivariate Analysis, Pedigree, Polymorphism, Single Nucleotide, Retinitis Pigmentosa diagnosis, Sequence Analysis, DNA, Extracellular Matrix Proteins genetics, Eye Proteins genetics, Genetic Loci, Genotyping Techniques methods, Membrane Proteins genetics, Nerve Tissue Proteins genetics, Retinitis Pigmentosa genetics
- Abstract
Purpose: Retinitis pigmentosa (RP) is the most common form of inherited blindness, caused by progressive degeneration of photoreceptor cells in the retina, and affects approximately 1 in 3,000 people. Over the past decade, significant progress has been made in gene therapy for RP and related diseases, making genetic characterization increasingly important. Recently, high-throughput technologies have provided an option for reasonably fast, cost-effective genetic characterization of autosomal recessive RP (arRP). The current study used a single nucleotide polymorphism (SNP) genotyping method to exclude up to 28 possible disease-causing genes in 31 non-consanguineous Australian families affected by arRP., Methods: DNA samples were collected from 59 individuals affected with arRP and 74 unaffected family members from 31 Australian families. Five to six SNPs were genotyped for 28 genes known to cause arRP or the related disease Leber congenital amaurosis (LCA). Cosegregation analyses were used to exclude possible causative genes from each of the 31 families. Bidirectional sequencing was used to identify disease-causing mutations in prioritized genes that were not excluded with cosegregation analyses., Results: Two families were excluded from analysis due to identification of false paternity. An average of 28.9% of genes were excluded per family when only one affected individual was available, in contrast to an average of 71.4% or 89.8% of genes when either two, or three or more affected individuals were analyzed, respectively. A statistically significant relationship between the proportion of genes excluded and the number of affected individuals analyzed was identified using a multivariate regression model (p<0.0001). Subsequent DNA sequencing resulted in identification of the likely disease-causing gene as CRB1 in one family (c.2548 G>A) and USH2A in two families (c.2276 G>T)., Conclusions: This study has shown that SNP genotyping cosegregation analysis can be successfully used to refine and expedite the genetic characterization of arRP in a non-consanguineous population; however, this method is effective only when DNA samples are available from more than one affected individual.
- Published
- 2012
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