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John R. Heckenlively - One of the best experts on this subject based on the ideXlab platform.
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corrigendum mutations in rdh12 encoding a photoreceptor cell retinol dehydrogenase cause severe childhood onset Retinal Dystrophy
Nature Genetics, 2004Co-Authors: Andreas R. Janecke, Debra A. Thompson, Christina L. Mchenry, Gerd Utermann, Christian Becker, Eduard Schmid, Anita R. Nair, Franz Rüschendorf, Christoph Hubner, John R. HeckenlivelyAbstract:Corrigendum: Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause severe childhood-onset Retinal Dystrophy
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Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe Retinal Dystrophy
Nature genetics, 2004Co-Authors: Andreas R. Janecke, Debra A. Thompson, Christina L. Mchenry, Gerd Utermann, Christian Becker, Christian A. Hübner, Eduard Schmid, Anita R. Nair, Franz Rüschendorf, John R. HeckenlivelyAbstract:We identified three consanguineous Austrian kindreds with 15 members affected by autosomal recessive childhood-onset severe Retinal Dystrophy, a genetically heterogeneous group of disorders characterized by degeneration of the photoreceptor cells. A whole-genome scan by microarray analysis of single-nucleotide polymorphisms (ref. 2) identified a founder haplotype and defined a critical interval of 1.53 cM on chromosome 14q23.3-q24.1 that contains the gene associated with this form of Retinal Dystrophy. RDH12 maps in this region and encodes a retinol dehydrogenase proposed to function in the visual cycle. A homozygous 677A-->G transition (resulting in Y226C) in RDH12 was present in all affected family members studied, as well as in two Austrian individuals with sporadic Retinal Dystrophy. We identified additional mutations in RDH12 in 3 of 89 non-Austrian individuals with Retinal Dystrophy: a 5-nucleotide deletion (806delCCCTG) and the transition 565C-->T (resulting in Q189X), each in the homozygous state, and 146C-->T (resulting in T49M) and 184C-->T (resulting in R62X) in compound heterozygosity. When expressed in COS-7 cells, Cys226 and Met49 variants had diminished and aberrant activity, respectively, in interconverting isomers of retinol and Retinal. The severe visual impairment of individuals with mutations in RDH12 is in marked contrast to the mild visual deficiency in individuals with fundus albipunctatus caused by mutations in RDH5, encoding another Retinal dehydrogenase. Our studies show that RDH12 is associated with Retinal Dystrophy and encodes an enzyme with a unique, nonredundant role in the photoreceptor cells.
Andrew R. Webster - One of the best experts on this subject based on the ideXlab platform.
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reanalysis of association of pro50leu substitution in guanylate cyclase activating protein 1 with dominant Retinal Dystrophy
JAMA Ophthalmology, 2020Co-Authors: Omar A Mahroo, Gavin Arno, Susan M Downes, Rola Baabbad, Alan C Bird, Andrew R. WebsterAbstract:Importance As genetic and genomic screening is becoming more widely accessed, correctly distinguishing pathogenic from nonpathogenic variants is of increasing relevance. Objective To reevaluate a previously reported family in whom the p.(Pro50Leu) variant in the geneGUCA1Awas associated with a dominant Retinal Dystrophy, in light of new examination findings in the proband’s daughter. Design, Setting, and Participants A genetic study relating to a family with an inherited Retinal Dystrophy was performed at the Retinal genetics service of Moorfields Eye Hospital from October 27, 2009, to May 23, 2019, after the proband’s daughter underwent fundus examination. Main Outcomes and Measures Results of sequencing of X chromosome–linked retinitis pigmentosa genes in the proband and specific analysis of the repetitive ORF15 region of theRPGRgene. Results A frame-shifting single-nucleotide deletion was found in the ORF15 exon ofRPGR(GRCh37 [hg19] x:38145160delT;NM_001034853.1: c.3092delA p.[Glu1031Glyfs*58]), which may be associated with the loss of 121 amino acid residues at the carboxyl terminus of the protein. The p.(Pro50Leu) variant inGUCA1Awas also found to be too common in a publicly available genome database to be a fully penetrant cause of a dominant Retinal Dystrophy. Conclusions and Relevance The phenotype in the family is now associated with the variant inRPGR. The findings suggest that the p.(Pro50Leu) variant inGUCA1Ashould not be regarded as pathogenic. This report also highlights the relevance of examining relatives, of reevaluating diagnoses in light of new data, and of considering X chromosome–linked inheritance in apparently autosomal dominant pedigrees unless there is clear male-to-male transmission.
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Whole-exome sequencing in the investigation of Retinal Dystrophy
The Lancet, 2016Co-Authors: Sarah Hull, Gavin Arno, Nicholas Owen, Vincent Plagnol, Graham E. Holder, Michel Michaelides, Anthony G. Robson, Andrew R. Webster, Anthony T. MooreAbstract:Abstract Background Juvenile onset Retinal Dystrophy presents at age 16 years or younger. It is genetically heterogeneous, and causal genes can be associated with distinctive clinical features. Next generation sequencing techniques including whole-exome sequencing (WES) provide an unbiased platform for investigating patients. The aim of this study was to perform WES on patients with early onset Retinal Dystrophy and conduct in-depth phenotyping to determine key clinical and molecular characteristics and correlations. Methods Patients were ascertained from the inherited Retinal clinics of a large tertiary referral centre. WES was performed on more than 100 probands. Likely pathogenic variants were confirmed with Sanger sequencing and family segregation. All patients underwent clinical examination, Retinal imaging and electrophysiological testing, and targeted systemic investigations. Written, informed consent was obtained from all participants. The study received approval from the local ethics committee. Findings Unusual features of genes previously reported to have systemic manifestations were observed in 12 families. These features included IFT140 -related Retinal Dystrophy in two families with no skeletal or renal manifestations of IFT140 -related Mainzer-Saldino syndrome, COL18A1 -related Retinal Dystrophy in a patient with normal neuroradiological imaging (unexpected for Knobloch syndrome), and IQCB1 in two patients with leber congenital amaurosis but normal renal function. In addition, identification of mutations in HPS6 in a family thought to have isolated foveal hypoplasia prompted further investigations that identified a bleeding diathesis consistent with Hermansky-Pudlak syndrome. Interpretation Early molecular diagnosis in early onset Retinal Dystrophy facilitates genetic counselling and directs appropriate investigations. WES provides an unbiased method for investigating patients compared with candidate gene sequencing and can identify atypical phenotypic presentations of syndromic genes as described in this cohort of patients. Thus, patient-specific investigations for potential systemic complications can be performed. Funding National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, Foundation Fighting Blindness, Fight For Sight, Moorfields Eye Hospital Special Trustees, Rosetrees Trust, Foundation Fighting Blindness Career Development Award (MM).
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lack of interphotoreceptor retinoid binding protein caused by homozygous mutation of rbp3 is associated with high myopia and Retinal Dystrophy
Investigative Ophthalmology & Visual Science, 2015Co-Authors: Gavin Arno, Sarah Hull, Vincent Plagnol, Graham E. Holder, Anthony G. Robson, Andrew R. Webster, Michael E Cheetham, Anthony T. MooreAbstract:PURPOSE: We present a detailed clinical and molecular study of four patients from two consanguineous families with a similar childhood-onset Retinal Dystrophy resulting from novel homozygous nonsense mutations in RBP3. METHODS: Four children with mutations in RBP3 encoding interphotoreceptor binding protein (IRBP) were ascertained by whole exome sequencing and subsequent direct Sanger sequencing. Detailed phenotyping was performed, including full clinical evaluation, electroretinography, fundus photography, fundus autofluorescence (FAF) imaging, and spectral-domain optical coherence tomography (OCT). RESULTS: Two novel homozygous nonsense mutations (c.1530T>A;p.Y510* and c.3454G>T;p.E1152*) in RBP3 were identified in four patients from two families. All four patients had a similar, unusual Retinal Dystrophy characterized by childhood onset high myopia, generalized rod and cone dysfunction, and an unremarkable fundus appearance. The FAF imaging showed multiple paracentral foci of low autofluorescence in one patient and patchy increased FAF in the region of the vascular arcades in another. The OCT showed loss of outer Retinal bands over peripheral macular areas in all 4 cases. CONCLUSIONS: To our knowledge, this report is the first to describe the Retinal Dystrophy in children caused by homozygous nonsense RBP3 mutations, highlighting the requirement for IRBP in normal eye development and visual function. Longitudinal study will reveal if the four children reported here will progress to a more typical retinitis pigmentosa phenotype described previously in adults with RBP3 mutations. The RBP3-related disease should be considered in children with high myopia and Retinal Dystrophy, particularly when there are no significant fundus changes.
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A homozygous mutation in the TUB gene associated with Retinal Dystrophy and obesity.
Human mutation, 2013Co-Authors: Arundhati Dev Borman, Andrew R. Webster, Donna S. Mackay, Robert H. Henderson, Naushin Waseem, Laura R. Pearce, Kerstin Nagel-wolfrum, Alice E. Davidson, Sumedha Garg, Vincent PlagnolAbstract:Inherited Retinal dystrophies are a major cause of childhood blindness. Here, we describe the identification of a homozygous frameshift mutation (c.1194_1195delAG, p.Arg398Serfs*9) in TUB in a child from a consanguineous UK Caucasian family investigated using autozygosity mapping and whole-exome sequencing. The proband presented with obesity, night blindness, decreased visual acuity, and electrophysiological features of a rod cone Dystrophy. The mutation was also found in two of the proband's siblings with Retinal Dystrophy and resulted in mislocalization of the truncated protein. In contrast to known forms of Retinal Dystrophy, including those caused by mutations in the tubby-like protein TULP-1, loss of function of TUB in the proband and two affected family members was associated with early-onset obesity, consistent with an additional role for TUB in energy homeostasis.
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understanding the impact of genetic testing for inherited Retinal Dystrophy
European Journal of Human Genetics, 2013Co-Authors: Ryan Combs, Andrew R. Webster, Anthony T. Moore, Marion Mcallister, Katherine Payne, J Lowndes, Sophie Devery, Susan M DownesAbstract:The capability of genetic technologies is expanding rapidly in the field of inherited eye disease. New genetic testing approaches will deliver a step change in the ability to diagnose and extend the possibility of targeted treatments. However, evidence is lacking about the benefits of genetic testing to support service planning. Here, we report qualitative data about Retinal Dystrophy families' experiences of genetic testing in United Kingdom. The data were part of a wider study examining genetic eye service provision. Twenty interviewees from families in which a causative mutation had been identified by a genetic eye clinic were recruited to the study. Fourteen interviewees had chosen to have a genetic test and five had not; one was uncertain. In-depth telephone interviews were conducted allowing a thorough exploration of interviewees' views and experiences of the benefits of genetic counselling and testing. Transcripts were analysed using thematic analysis. Both affected and unaffected interviewees expressed mainly positive views about genetic testing, highlighting benefits such as diagnostic confirmation, risk information, and better preparation for the future. Negative consequences included the burden of knowledge, moral dilemmas around reproduction, and potential impact on insurance. The offer of genetic testing was often taken up, but was felt unnecessary in some cases. Interviewees in the study reported many benefits, suggesting genetic testing should be available to this patient group. The benefits and risks identified will inform future evaluation of models of service delivery. This research was part of a wider study exploring experiences of families with Retinal Dystrophy.
Debra A. Thompson - One of the best experts on this subject based on the ideXlab platform.
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corrigendum mutations in rdh12 encoding a photoreceptor cell retinol dehydrogenase cause severe childhood onset Retinal Dystrophy
Nature Genetics, 2004Co-Authors: Andreas R. Janecke, Debra A. Thompson, Christina L. Mchenry, Gerd Utermann, Christian Becker, Eduard Schmid, Anita R. Nair, Franz Rüschendorf, Christoph Hubner, John R. HeckenlivelyAbstract:Corrigendum: Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause severe childhood-onset Retinal Dystrophy
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Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe Retinal Dystrophy
Nature genetics, 2004Co-Authors: Andreas R. Janecke, Debra A. Thompson, Christina L. Mchenry, Gerd Utermann, Christian Becker, Christian A. Hübner, Eduard Schmid, Anita R. Nair, Franz Rüschendorf, John R. HeckenlivelyAbstract:We identified three consanguineous Austrian kindreds with 15 members affected by autosomal recessive childhood-onset severe Retinal Dystrophy, a genetically heterogeneous group of disorders characterized by degeneration of the photoreceptor cells. A whole-genome scan by microarray analysis of single-nucleotide polymorphisms (ref. 2) identified a founder haplotype and defined a critical interval of 1.53 cM on chromosome 14q23.3-q24.1 that contains the gene associated with this form of Retinal Dystrophy. RDH12 maps in this region and encodes a retinol dehydrogenase proposed to function in the visual cycle. A homozygous 677A-->G transition (resulting in Y226C) in RDH12 was present in all affected family members studied, as well as in two Austrian individuals with sporadic Retinal Dystrophy. We identified additional mutations in RDH12 in 3 of 89 non-Austrian individuals with Retinal Dystrophy: a 5-nucleotide deletion (806delCCCTG) and the transition 565C-->T (resulting in Q189X), each in the homozygous state, and 146C-->T (resulting in T49M) and 184C-->T (resulting in R62X) in compound heterozygosity. When expressed in COS-7 cells, Cys226 and Met49 variants had diminished and aberrant activity, respectively, in interconverting isomers of retinol and Retinal. The severe visual impairment of individuals with mutations in RDH12 is in marked contrast to the mild visual deficiency in individuals with fundus albipunctatus caused by mutations in RDH5, encoding another Retinal dehydrogenase. Our studies show that RDH12 is associated with Retinal Dystrophy and encodes an enzyme with a unique, nonredundant role in the photoreceptor cells.
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mutations in rpe65 cause autosomal recessive childhood onset severe Retinal Dystrophy
Nature Genetics, 1997Co-Authors: Debra A. Thompson, Ulrich Finckh, Birgit Lorenz, C Srisailapathy R Srikumari, Aileen Nicoletti, K R Murthy, Michaela Rathmann, Govindasamy Kumaramanickavel, Michael J Denton, Andreas GalAbstract:Autosomal recessive childhood-onset severe Retinal Dystrophy (arCSRD) designates a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously1. The most severe cases are termed Leber congenital amaurosis (LCA), while the less aggressive forms are usually considered juvenile retinitis pigmentosa. Recently, mutations in the Retinal-specific guanylate cyclase gene were found in patients with LCA2. Disease genes implicated in other forms of arCSRD are expected to encode proteins present in the neuroretina or in the Retinal pigment epithelium (RPE). The RPE, a monolayer of cells separating the vascular-rich choroid and the neuroretina, is in intimate contact with the outer segments of rods and cones via the microvilli surrounding the photoreceptors. The RPE expresses a tissue-specific and evolutionary highly conserved 61 kD protein (RPE65) present at high levels in vivo3–6. Although the function of RPE65 is not yet known, an important role in the RPE/photoreceptor vitamin-A cycle is suggested by the fact that RPE65 associates both with serum retinol-binding protein7,8 and with the RPE-specific 11-cis retinol dehydrogenase, an enzyme active in the synthesis of the visual pigment chromophore 11-cis Retinal9. Here we report that the analysis of RPE65 in a collection of about 100 unselected Retinal-Dystrophy patients of different ethnic origin revealed five that are likely to be pathogenic mutations, including a missense mutation (Pro363Thr), two point mutations affecting splicing (912+1G→T and 65+5G→A) and two small re-arrangements (ins144T and 831del8) on a total of nine alleles of five patients with arCSRD. In contrast to other genes whose defects have been implicated in degenerative retinopathies, RPE65 is the first disease gene in this group of inherited disorders that is expressed exclusively in the RPE, and may play a role in vitamin-A metabolism of the retina.
Sarah Hull - One of the best experts on this subject based on the ideXlab platform.
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association of steroid 5α reductase type 3 congenital disorder of glycosylation with early onset Retinal Dystrophy
JAMA Ophthalmology, 2017Co-Authors: Rachel L Taylor, Kamron N Khan, Jiten Morarji, Sarah Hull, James A Poulter, Gavin Arno, Nikolas PontikosAbstract:Importance: Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a rare disorder of N-linked glycosylation. Its Retinal phenotype is not well described but could be important for disease recognition because it appears to be a consistent primary presenting feature. Objective: To investigate a series of patients with the same mutation in the SRD5A3 gene and thereby characterize its Retinal manifestations and other associated features. Design, Setting and Participants: Seven affected individuals from 4 unrelated families with early-onset Retinal Dystrophy as a primary manifestation underwent comprehensive ophthalmic assessment, including Retinal imaging and electrodiagnostic testing. Developmental and systemic findings were also recorded. Molecular genetic approaches, including targeted next-generation sequencing, autozygosity mapping, and apex microarray, were tried to reach a diagnosis; all participants were mutation negative. Whole-exome sequencing or whole-genome sequencing was used to identify the causative variant. Biochemical profiling was conducted to confirm a CDG type I defect. Patient phenotype data were collected over the course of ophthalmic follow-up, spanning a period of 20 years, beginning March 20, 1997, through September 15, 2016. Main Outcomes and Measures: Detailed clinical phenotypes as well as genetic and biochemical results. Results: The cohort consisted of 7 participants (5 females and 2 males) whose mean (SD) age at the most recent examination was 17.1 (3.9) years and who were all of South Asian ethnicity. Whole-exome sequencing and whole-genome sequencing identified the same homozygous SRD5A3 c.57G>A, p.(Trp19Ter) variant as the underlying cause of early-onset Retinal Dystrophy in each family. Detailed ocular phenotyping identified early-onset (aged ≤3 years) visual loss (mean [SD] best-corrected visual acuity, +0.95 [0.34] logMAR [20/180 Snellen]), childhood-onset nyctalopia, myopia (mean [SD] refractive error, -6.71 [-4.22]), and nystagmus. Six of the 7 patients had learning difficulties and psychomotor delay. Fundus autofluorescence imaging and optical coherence tomographic scans were abnormal in all patients, and electrodiagnostic testing revealed rod and cone dysfunction in the 5 patients tested. Conclusions and Relevance: Mutations in the SRD5A3 gene may cause early-onset Retinal Dystrophy, a previously underdescribed feature of the SRD5A3-CDG disorder that is progressive and may lead to serious visual impairment. SRD5A3 and other glycosylation disorder genes should be considered as a cause of Retinal Dystrophy even when systemic features are mild. Further delineation of SRD5A3-associated eye phenotypes can help inform genetic counseling for prognostic estimation of visual loss and disease progression.
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preserved visual function in Retinal Dystrophy due to hypomorphic rpe65 mutations
British Journal of Ophthalmology, 2016Co-Authors: Sarah Hull, Graham E. Holder, Michel Michaelides, Anthony G. Robson, Rajarshi MukherjeeAbstract:Background/aims To present detailed phenotypic and molecular findings in four patients from four families with atypical, mild, recessive RPE65 -related Retinal Dystrophy and discuss potential implications for gene replacement therapy. Methods Four patients from four families with early onset Retinal Dystrophy underwent clinical examination, Retinal imaging and electrophysiological testing. Bidirectional Sanger sequencing of all exons and intron–exon boundaries of RPE65 was performed. Results All patients presented with nyctalopia in early childhood but demonstrated a mild phenotype with good visual acuity until at least 19 years of age. All had generalised Retinal dysfunction on electroretinography. Central macular thickness on optical coherence tomography was preserved in those patients with good visual acuity. One patient had extensive white dots throughout the retina reminiscent of fundus albipunctatus with electrophysiological evidence of partial recovery of rod function after prolonged dark adaptation. Sanger sequencing identified RPE65 mutations in all patients including three missense variants likely to represent hypomorphic alleles. Conclusions Hypomorphic mutations of RPE65 are associated with mild disease in childhood with preservation of good visual acuity into adulthood; they may in rare cases be associated with a flecked retina appearance similar to fundus albipunctatus. The presence of normal visual acuity in patients with hypomorphic mutations in RPE65 suggests that efficiency of transduction may not be the limiting factor in improving visual acuity in trials of gene replacement therapy. Rather, it suggests that for optimal recovery of visual acuity gene replacement therapy may need to be given much earlier in childhood.
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Nonsyndromic Retinal Dystrophy due to Bi-Allelic Mutations in the Ciliary Transport Gene IFT140.
Investigative Ophthalmology & Visual Science, 2016Co-Authors: Sarah Hull, Nicholas Owen, Farrah Islam, Dhani Tracey-white, Vincent Plagnol, Graham E. Holder, Michel Michaelides, Keren J. Carss, F. Lucy Raymond, Jean-michel RozetAbstract:PURPOSE: Mutations in the ciliary transporter gene IFT140, usually associated with a severe syndromic ciliopathy, may also cause isolated Retinal Dystrophy. A series of patients with nonsyndromic retinitis pigmentosa (RP) due to IFT140 was investigated in this study. METHODS: Five probands and available affected family members underwent detailed phenotyping including Retinal imaging and electrophysiology. Whole exome sequencing was performed on two probands, a targeted sequencing panel of 176 Retinal genes on a further two, and whole genome sequencing on the fifth. Missense mutations of IFT140 were further investigated in vitro using transient plasmid transfection of hTERT-RPE1 cells. RESULTS: Eight affected patients from five families had preserved visual acuity until at least the second decade; all had normal development without skeletal manifestations or renal failure at age 13 to 67 years (mean, 42 years; median, 44.5 years). Bi-allelic mutations in IFT140 were identified in all families including two novel mutations: c.2815T > C (p.Ser939Pro) and c.1422_23insAA (p.Arg475Asnfs*14). Expression studies demonstrated a significantly reduced number of cells showing localization of mutant IFT140 with the basal body for two nonsyndromic mutations and two syndromic mutations compared with the wild type and a polymorphism. CONCLUSIONS: This study highlights the phenotype of nonsyndromic RP due to mutations in IFT140 with milder Retinal Dystrophy than that associated with the syndromic disease.
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Whole-exome sequencing in the investigation of Retinal Dystrophy
The Lancet, 2016Co-Authors: Sarah Hull, Gavin Arno, Nicholas Owen, Vincent Plagnol, Graham E. Holder, Michel Michaelides, Anthony G. Robson, Andrew R. Webster, Anthony T. MooreAbstract:Abstract Background Juvenile onset Retinal Dystrophy presents at age 16 years or younger. It is genetically heterogeneous, and causal genes can be associated with distinctive clinical features. Next generation sequencing techniques including whole-exome sequencing (WES) provide an unbiased platform for investigating patients. The aim of this study was to perform WES on patients with early onset Retinal Dystrophy and conduct in-depth phenotyping to determine key clinical and molecular characteristics and correlations. Methods Patients were ascertained from the inherited Retinal clinics of a large tertiary referral centre. WES was performed on more than 100 probands. Likely pathogenic variants were confirmed with Sanger sequencing and family segregation. All patients underwent clinical examination, Retinal imaging and electrophysiological testing, and targeted systemic investigations. Written, informed consent was obtained from all participants. The study received approval from the local ethics committee. Findings Unusual features of genes previously reported to have systemic manifestations were observed in 12 families. These features included IFT140 -related Retinal Dystrophy in two families with no skeletal or renal manifestations of IFT140 -related Mainzer-Saldino syndrome, COL18A1 -related Retinal Dystrophy in a patient with normal neuroradiological imaging (unexpected for Knobloch syndrome), and IQCB1 in two patients with leber congenital amaurosis but normal renal function. In addition, identification of mutations in HPS6 in a family thought to have isolated foveal hypoplasia prompted further investigations that identified a bleeding diathesis consistent with Hermansky-Pudlak syndrome. Interpretation Early molecular diagnosis in early onset Retinal Dystrophy facilitates genetic counselling and directs appropriate investigations. WES provides an unbiased method for investigating patients compared with candidate gene sequencing and can identify atypical phenotypic presentations of syndromic genes as described in this cohort of patients. Thus, patient-specific investigations for potential systemic complications can be performed. Funding National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, Foundation Fighting Blindness, Fight For Sight, Moorfields Eye Hospital Special Trustees, Rosetrees Trust, Foundation Fighting Blindness Career Development Award (MM).
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lack of interphotoreceptor retinoid binding protein caused by homozygous mutation of rbp3 is associated with high myopia and Retinal Dystrophy
Investigative Ophthalmology & Visual Science, 2015Co-Authors: Gavin Arno, Sarah Hull, Vincent Plagnol, Graham E. Holder, Anthony G. Robson, Andrew R. Webster, Michael E Cheetham, Anthony T. MooreAbstract:PURPOSE: We present a detailed clinical and molecular study of four patients from two consanguineous families with a similar childhood-onset Retinal Dystrophy resulting from novel homozygous nonsense mutations in RBP3. METHODS: Four children with mutations in RBP3 encoding interphotoreceptor binding protein (IRBP) were ascertained by whole exome sequencing and subsequent direct Sanger sequencing. Detailed phenotyping was performed, including full clinical evaluation, electroretinography, fundus photography, fundus autofluorescence (FAF) imaging, and spectral-domain optical coherence tomography (OCT). RESULTS: Two novel homozygous nonsense mutations (c.1530T>A;p.Y510* and c.3454G>T;p.E1152*) in RBP3 were identified in four patients from two families. All four patients had a similar, unusual Retinal Dystrophy characterized by childhood onset high myopia, generalized rod and cone dysfunction, and an unremarkable fundus appearance. The FAF imaging showed multiple paracentral foci of low autofluorescence in one patient and patchy increased FAF in the region of the vascular arcades in another. The OCT showed loss of outer Retinal bands over peripheral macular areas in all 4 cases. CONCLUSIONS: To our knowledge, this report is the first to describe the Retinal Dystrophy in children caused by homozygous nonsense RBP3 mutations, highlighting the requirement for IRBP in normal eye development and visual function. Longitudinal study will reveal if the four children reported here will progress to a more typical retinitis pigmentosa phenotype described previously in adults with RBP3 mutations. The RBP3-related disease should be considered in children with high myopia and Retinal Dystrophy, particularly when there are no significant fundus changes.
Michel Michaelides - One of the best experts on this subject based on the ideXlab platform.
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preserved visual function in Retinal Dystrophy due to hypomorphic rpe65 mutations
British Journal of Ophthalmology, 2016Co-Authors: Sarah Hull, Graham E. Holder, Michel Michaelides, Anthony G. Robson, Rajarshi MukherjeeAbstract:Background/aims To present detailed phenotypic and molecular findings in four patients from four families with atypical, mild, recessive RPE65 -related Retinal Dystrophy and discuss potential implications for gene replacement therapy. Methods Four patients from four families with early onset Retinal Dystrophy underwent clinical examination, Retinal imaging and electrophysiological testing. Bidirectional Sanger sequencing of all exons and intron–exon boundaries of RPE65 was performed. Results All patients presented with nyctalopia in early childhood but demonstrated a mild phenotype with good visual acuity until at least 19 years of age. All had generalised Retinal dysfunction on electroretinography. Central macular thickness on optical coherence tomography was preserved in those patients with good visual acuity. One patient had extensive white dots throughout the retina reminiscent of fundus albipunctatus with electrophysiological evidence of partial recovery of rod function after prolonged dark adaptation. Sanger sequencing identified RPE65 mutations in all patients including three missense variants likely to represent hypomorphic alleles. Conclusions Hypomorphic mutations of RPE65 are associated with mild disease in childhood with preservation of good visual acuity into adulthood; they may in rare cases be associated with a flecked retina appearance similar to fundus albipunctatus. The presence of normal visual acuity in patients with hypomorphic mutations in RPE65 suggests that efficiency of transduction may not be the limiting factor in improving visual acuity in trials of gene replacement therapy. Rather, it suggests that for optimal recovery of visual acuity gene replacement therapy may need to be given much earlier in childhood.
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phenotypic features of crb1 associated early onset severe Retinal Dystrophy and the different molecular approaches to identifying the disease causing variants
Graefes Archive for Clinical and Experimental Ophthalmology, 2016Co-Authors: Bohdan Kousal, Michel Michaelides, Lubica Dudakova, Renata Gaillyova, Michaela Hejtmankova, Pavel Diblik, Petra LiskovaAbstract:Purpose The aim of this study was to determine the molecular genetic basis of an early-onset severe Retinal Dystrophy in three unrelated consecutive patients of Czech origin and to describe their ocular phenotype.
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Nonsyndromic Retinal Dystrophy due to Bi-Allelic Mutations in the Ciliary Transport Gene IFT140.
Investigative Ophthalmology & Visual Science, 2016Co-Authors: Sarah Hull, Nicholas Owen, Farrah Islam, Dhani Tracey-white, Vincent Plagnol, Graham E. Holder, Michel Michaelides, Keren J. Carss, F. Lucy Raymond, Jean-michel RozetAbstract:PURPOSE: Mutations in the ciliary transporter gene IFT140, usually associated with a severe syndromic ciliopathy, may also cause isolated Retinal Dystrophy. A series of patients with nonsyndromic retinitis pigmentosa (RP) due to IFT140 was investigated in this study. METHODS: Five probands and available affected family members underwent detailed phenotyping including Retinal imaging and electrophysiology. Whole exome sequencing was performed on two probands, a targeted sequencing panel of 176 Retinal genes on a further two, and whole genome sequencing on the fifth. Missense mutations of IFT140 were further investigated in vitro using transient plasmid transfection of hTERT-RPE1 cells. RESULTS: Eight affected patients from five families had preserved visual acuity until at least the second decade; all had normal development without skeletal manifestations or renal failure at age 13 to 67 years (mean, 42 years; median, 44.5 years). Bi-allelic mutations in IFT140 were identified in all families including two novel mutations: c.2815T > C (p.Ser939Pro) and c.1422_23insAA (p.Arg475Asnfs*14). Expression studies demonstrated a significantly reduced number of cells showing localization of mutant IFT140 with the basal body for two nonsyndromic mutations and two syndromic mutations compared with the wild type and a polymorphism. CONCLUSIONS: This study highlights the phenotype of nonsyndromic RP due to mutations in IFT140 with milder Retinal Dystrophy than that associated with the syndromic disease.
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Whole-exome sequencing in the investigation of Retinal Dystrophy
The Lancet, 2016Co-Authors: Sarah Hull, Gavin Arno, Nicholas Owen, Vincent Plagnol, Graham E. Holder, Michel Michaelides, Anthony G. Robson, Andrew R. Webster, Anthony T. MooreAbstract:Abstract Background Juvenile onset Retinal Dystrophy presents at age 16 years or younger. It is genetically heterogeneous, and causal genes can be associated with distinctive clinical features. Next generation sequencing techniques including whole-exome sequencing (WES) provide an unbiased platform for investigating patients. The aim of this study was to perform WES on patients with early onset Retinal Dystrophy and conduct in-depth phenotyping to determine key clinical and molecular characteristics and correlations. Methods Patients were ascertained from the inherited Retinal clinics of a large tertiary referral centre. WES was performed on more than 100 probands. Likely pathogenic variants were confirmed with Sanger sequencing and family segregation. All patients underwent clinical examination, Retinal imaging and electrophysiological testing, and targeted systemic investigations. Written, informed consent was obtained from all participants. The study received approval from the local ethics committee. Findings Unusual features of genes previously reported to have systemic manifestations were observed in 12 families. These features included IFT140 -related Retinal Dystrophy in two families with no skeletal or renal manifestations of IFT140 -related Mainzer-Saldino syndrome, COL18A1 -related Retinal Dystrophy in a patient with normal neuroradiological imaging (unexpected for Knobloch syndrome), and IQCB1 in two patients with leber congenital amaurosis but normal renal function. In addition, identification of mutations in HPS6 in a family thought to have isolated foveal hypoplasia prompted further investigations that identified a bleeding diathesis consistent with Hermansky-Pudlak syndrome. Interpretation Early molecular diagnosis in early onset Retinal Dystrophy facilitates genetic counselling and directs appropriate investigations. WES provides an unbiased method for investigating patients compared with candidate gene sequencing and can identify atypical phenotypic presentations of syndromic genes as described in this cohort of patients. Thus, patient-specific investigations for potential systemic complications can be performed. Funding National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, Foundation Fighting Blindness, Fight For Sight, Moorfields Eye Hospital Special Trustees, Rosetrees Trust, Foundation Fighting Blindness Career Development Award (MM).