The Experts below are selected from a list of 213 Experts worldwide ranked by ideXlab platform
Alexander N Yatsenko - One of the best experts on this subject based on the ideXlab platform.
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high resolution microarray analysis unravels complex xq28 aberrations in patients and carriers affected by x linked blue cone monochromacy
Clinical Genetics, 2016Co-Authors: Svetlana A Yatsenko, Barbara J Jennings, Heather A Bakos, Kathleen Vitullo, Marina Kedrov, Archana Kishore, Michelle A Woodtrageser, Stephen Cercone, Urvashi Surti, Alexander N YatsenkoAbstract:A loss-of-function of both the OPN1LW (red) and OPN1MW (green) cone opsin photopigment genes causes blue cone monochromacy (BCM; OMIM#303700), a rare X-linked, recessive disorder characterized by markedly reduced vision, severe photophobia, congenital nystagmus, and inability to discriminate colors. In humans, up to nine copies of the OPN1LW and OPN1MW genes are arranged in a 5′ −3′ orientation within Xq28, forming the cluster (1–3). The close physical location and high (99.8%) sequence homology predispose this genomic region to non-allelic homologous recombination, which results in deletions, duplications, and the formation of OPN1LW/OPN1MW-hybrid genes (4–6). In the normal human retina, only the most proximal two genes in the cluster are expressed (2). Red or green expression in cone photoreceptors is accomplished by interaction of the gene promoter with a locus control region (LCR), a unique cis-regulatory DNA sequence located ~4 kb upstream of OPN1LW (7). In about 90% of males affected by BCM, Xq28 deletions or point mutations inactivating both OPN1LW and OPN1MW have been identified by polymerase chain reaction (PCR)-based molecular testing, while ~10% of patients have negative results and the molecular defects remain unknown (2, 6), precluding accurate information on disease progression in affected males and female carriers, carrier and prenatal testing, potential approaches, and efficiency of gene therapy. The Xq28 deletions may remove the LCR, inactivating both wild-type opsin genes, or extend into the opsin cluster (4, 6). The complex structure of the LCR and opsin genes, the presence of highly homologous sequences, and variability within the opsin genomic region among human populations pose multiple challenges and limit the effectiveness of diagnostic and carrier testing in families with BCM. Microarray platforms are now used extensively for diagnosis and research to detect genomic imbalances contributing to human disease and population diversity (8, 9). High-resolution microarrays provide distinct benefits in studying males affected with X-linked disorders (9). Single gene alterations are more likely to be present in affected males; however, the resolution of clinical whole-genome microarray platforms, ranging from 25–200 kb, is often insufficient to detect smaller X-chromosome imbalances. We identified novel molecular alterations in three BCM families, using high-resolution X chromosome-targeted (X-HR) array comparative genomic hybridization (aCGH) and report the advantages and limitations of microarray analysis in the diagnosis of BCM and other X-linked conditions.
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High‐resolution microarray analysis unravels complex Xq28 aberrations in patients and carriers affected by X‐linked blue cone monochromacy
Clinical Genetics, 2015Co-Authors: Svetlana A Yatsenko, Barbara J Jennings, Heather A Bakos, Kathleen Vitullo, Marina Kedrov, Archana Kishore, Stephen Cercone, Michelle A. Wood-trageser, Urvashi Surti, Alexander N YatsenkoAbstract:A loss-of-function of both the OPN1LW (red) and OPN1MW (green) cone opsin photopigment genes causes blue cone monochromacy (BCM; OMIM#303700), a rare X-linked, recessive disorder characterized by markedly reduced vision, severe photophobia, congenital nystagmus, and inability to discriminate colors. In humans, up to nine copies of the OPN1LW and OPN1MW genes are arranged in a 5′ −3′ orientation within Xq28, forming the cluster (1–3). The close physical location and high (99.8%) sequence homology predispose this genomic region to non-allelic homologous recombination, which results in deletions, duplications, and the formation of OPN1LW/OPN1MW-hybrid genes (4–6). In the normal human retina, only the most proximal two genes in the cluster are expressed (2). Red or green expression in cone photoreceptors is accomplished by interaction of the gene promoter with a locus control region (LCR), a unique cis-regulatory DNA sequence located ~4 kb upstream of OPN1LW (7). In about 90% of males affected by BCM, Xq28 deletions or point mutations inactivating both OPN1LW and OPN1MW have been identified by polymerase chain reaction (PCR)-based molecular testing, while ~10% of patients have negative results and the molecular defects remain unknown (2, 6), precluding accurate information on disease progression in affected males and female carriers, carrier and prenatal testing, potential approaches, and efficiency of gene therapy. The Xq28 deletions may remove the LCR, inactivating both wild-type opsin genes, or extend into the opsin cluster (4, 6). The complex structure of the LCR and opsin genes, the presence of highly homologous sequences, and variability within the opsin genomic region among human populations pose multiple challenges and limit the effectiveness of diagnostic and carrier testing in families with BCM. Microarray platforms are now used extensively for diagnosis and research to detect genomic imbalances contributing to human disease and population diversity (8, 9). High-resolution microarrays provide distinct benefits in studying males affected with X-linked disorders (9). Single gene alterations are more likely to be present in affected males; however, the resolution of clinical whole-genome microarray platforms, ranging from 25–200 kb, is often insufficient to detect smaller X-chromosome imbalances. We identified novel molecular alterations in three BCM families, using high-resolution X chromosome-targeted (X-HR) array comparative genomic hybridization (aCGH) and report the advantages and limitations of microarray analysis in the diagnosis of BCM and other X-linked conditions.
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High‐resolution microarray analysis unravels complex Xq28 aberrations in patients and carriers affected by X‐linked blue cone monochromacy
Clinical genetics, 2015Co-Authors: Svetlana A Yatsenko, Barbara J Jennings, Heather A Bakos, Kathleen Vitullo, Marina Kedrov, Archana Kishore, Stephen Cercone, Michelle A. Wood-trageser, Urvashi Surti, Alexander N YatsenkoAbstract:The human X chromosome contains ∼ 1600 genes, about 15% of which have been associated with a specific genetic condition, mainly affecting males. Blue cone monochromacy (BCM) is an X-linked condition caused by a loss-of-function of both the OPN1LW and OPN1MW opsin genes. The cone opsin gene cluster is composed of 2-9 paralogs with 99.8% sequence homology and is susceptible to deletions, duplications, and mutations. Current diagnostic tests employ polymerase chain reaction (PCR)-based technologies; however, alterations remain undetermined in 10% of patients. Furthermore, carrier testing in females is limited or unavailable. High-resolution X chromosome-targeted CGH microarray was applied to test for rearrangements in males with BCM and female carriers from three unrelated families. Pathogenic alterations were revealed in all probands, characterized by sequencing of the breakpoint junctions and quantitative real-time PCR. In two families, we identified a novel founder mutation that consisted of a complex 3-kb deletion that embraced the cis-regulatory locus control region and insertion of an additional aberrant OPN1MW gene. The application of high-resolution X-chromosome microarray in clinical diagnosis brings significant advantages in detection of small aberrations that are beyond the resolution of clinically available aCGH analysis and which can improve molecular diagnosis of the known conditions and unravel previously unrecognized X-linked diseases.
Jessica C Gardner - One of the best experts on this subject based on the ideXlab platform.
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residual cone structure in patients with x linked cone opsin mutations
Investigative Ophthalmology & Visual Science, 2018Co-Authors: Emily J Patterson, Angelos Kalitzeos, Melissa Kasilian, Jessica C Gardner, Jay Neitz, Alison J. HardcastleAbstract:Purpose To assess residual cone structure in subjects with mutations in exon 2, 3, and 4 of the OPN1LW or OPN1MW opsin. Methods Thirteen males had their OPN1LW/OPN1MW opsin genes characterized. The cone mosaic was imaged using both confocal and nonconfocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO), and retinal thickness was evaluated using optical coherence tomography (OCT). Six subjects completed serial imaging over a maximum period of 18 months and cone density was measured across imaging sessions. Results Ten subjects had an OPN1LW/OPN1MW "interchange" opsin mutation designated as LIAVA or LVAVA, which both introduce exon 3 splicing defects leading to a lack of functional photopigment in cones expressing LIAVA and greatly reduced functional photopigment in cones expressing LVAVA. Despite disrupted cone reflectivity and reduced numerosity, residual inner segments could be visualized. Similar patterns were observed in individuals with an exon 2 insertion, or an exon 4 splice defect, both of which are also expected to produce cones that are devoid of functional opsin protein. OCT revealed variably reduced retinal thickness. A significant inverse relationship was found between the proportion of waveguiding cones and axial length. Conclusions Split-detection imaging revealed that the altered appearance of the cone mosaic in confocal images for subjects with exon 2, 3, and 4 mutations was generally due to disrupted waveguiding, rather than structural loss, making them possible candidates for gene therapy to restore cone function. The relative fraction of waveguiding cones was highly variable across subjects, which appears to influence emmetropization in these subjects.
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Cone opsins, colour blindness and cone dystrophy: Genotype-phenotype correlations.
South African Medical Journal, 2016Co-Authors: Jessica C Gardner, Michel Michaelides, Alison J. HardcastleAbstract:X-linked cone photoreceptor disorders caused by mutations in the OPN1LW (L) and OPN1MW (M) cone opsin genes on chromosome Xq28 include a range of conditions from mild stable red-green colour vision deficiencies to severe cone dystrophies causing progressive loss of vision and blindness. Advances in molecular genotyping and functional analyses of causative variants, combined with deep retinal phenotyping, are unravelling genetic mechanisms underlying the variability of cone opsin disorders.
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Three different cone opsin gene array mutational mechanisms with genotype-phenotype correlation and functional investigation of cone opsin variants.
Human mutation, 2014Co-Authors: Jessica C Gardner, Hisao Ueyama, Gerald Liew, Yinghua Quan, Burcu Ermetal, Alice E. Davidson, Nele Schwarz, Naheed Kanuga, Ravinder K. Chana, Eamonn R. MaherAbstract:Mutations in the OPN1LW (L-) and OPN1MW (M-)cone opsin genes underlie a spectrum of cone photoreceptor defects from stationary loss of color vision to progressive retinal degeneration. Genotypes of 22 families with a range of cone disorders were grouped into three classes: deletions of the locus control region (LCR); missense mutation (p.Cys203Arg) in an L-/M-hybrid gene; and exon 3 single-nucleotide polymorphism (SNP) interchange haplotypes in an otherwise normal gene array. Moderate-to-high myopia was observed in all mutation categories. Individuals with LCR deletions or p.Cys203Arg mutations were more likely to have nystagmus and poor vision, with disease progression in some p.Cys203Arg patients. Three disease-associated exon 3 SNP haplotypes encoding LIAVA, LVAVA, or MIAVA were identified in our cohort. These patients were less likely to have nystagmus but more likely to show progression, with all patients over the age of 40 years having marked macular abnormalities. Previously, the haplotype LIAVA has been shown to result in exon 3 skipping. Here, we show that haplotypes LVAVA and MIAVA also result in aberrant splicing, with a residual low level of correctly spliced cone opsin. The OPN1LW/OPN1MW:c.532A>G SNP, common to all three disease-associated haplotypes, appears to be principally responsible for this mutational mechanism.
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Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy.
Human Gene Therapy, 2013Co-Authors: Artur V Cideciyan, Michel Michaelides, Alexander Sumaroka, Megan E. Land, Sharon B Schwartz, Robert B Hufnagel, Alfredo Dubra, Joseph Carroll, Jessica C GardnerAbstract:Human X-linked blue-cone monochromacy (BCM), a disabling congenital visual disorder of cone photoreceptors, is a candidate disease for gene augmentation therapy. BCM is caused by either mutations in the red (OPN1LW) and green (OPN1MW) cone photoreceptor opsin gene array or large deletions encompassing portions of the gene array and upstream regulatory sequences that would predict a lack of red or green opsin expression. The fate of opsin-deficient cone cells is unknown. We know that rod opsin null mutant mice show rapid postnatal death of rod photoreceptors. Using in vivo histology with high-resolution retinal imaging, we studied a cohort of 20 BCM patients (age range 5–58) with large deletions in the red/green opsin gene array. Already in the first years of life, retinal structure was not normal: there was partial loss of photoreceptors across the central retina. Remaining cone cells had detectable outer segments that were abnormally shortened. Adaptive optics imaging confirmed the existence of inner segments at a spatial density greater than that expected for the residual blue cones. The evidence indicates that human cones in patients with deletions in the red/green opsin gene array can survive in reduced numbers with limited outer segment material, suggesting potential value of gene therapy for BCM.
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the effect of cone opsin mutations on retinal structure and the integrity of the photoreceptor mosaic
Investigative Ophthalmology & Visual Science, 2012Co-Authors: Joseph Carroll, Jessica C Gardner, Liliana Mizrahimeissonnier, Rick N Nordgren, Mohamed A. Genead, Robert F Cooper, Alfredo Dubra, Thomas B Connor, Adam M Dubis, Kimberly E StepienAbstract:RESULTS. While disruptions in retinal lamination and cone mosaic structure were observed in all subjects, genotypespecific differences were also observed. For example, subjects with ‘‘L/M interchange’’ mutations resulting from intermixing of ancestral OPN1LW and OPN1MW genes had significant residual cone structure in the parafovea (~25% of normal), despite widespread retinal disruption that included a large foveal lesion and thinning of the parafoveal inner retina. These subjects also reported a later-onset, progressive loss of visual function. In contrast, subjects with the C203R missense mutation presented with congenital blue cone monochromacy, with retinal lamination defects being restricted to the ONLþHFL and the degree of residual cone structure (8% of normal) being consistent with that expected for the S-cone submosaic. CONCLUSIONS. The photoreceptor phenotype associated with OPN1LW and OPN1MW mutations is highly variable. These findings have implications for the potential restoration of visual function in subjects with opsin mutations. Our study highlights the importance of high-resolution phenotyping to characterize cellular structure in inherited retinal disease; such information will be critical for selecting patients most likely to respond to therapeutic intervention and for establishing a baseline for evaluating treatment efficacy. (Invest Ophthalmol Vis Sci. 2012;53:8006–8015) DOI:10.1167/iovs.12-11087
Svetlana A Yatsenko - One of the best experts on this subject based on the ideXlab platform.
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high resolution microarray analysis unravels complex xq28 aberrations in patients and carriers affected by x linked blue cone monochromacy
Clinical Genetics, 2016Co-Authors: Svetlana A Yatsenko, Barbara J Jennings, Heather A Bakos, Kathleen Vitullo, Marina Kedrov, Archana Kishore, Michelle A Woodtrageser, Stephen Cercone, Urvashi Surti, Alexander N YatsenkoAbstract:A loss-of-function of both the OPN1LW (red) and OPN1MW (green) cone opsin photopigment genes causes blue cone monochromacy (BCM; OMIM#303700), a rare X-linked, recessive disorder characterized by markedly reduced vision, severe photophobia, congenital nystagmus, and inability to discriminate colors. In humans, up to nine copies of the OPN1LW and OPN1MW genes are arranged in a 5′ −3′ orientation within Xq28, forming the cluster (1–3). The close physical location and high (99.8%) sequence homology predispose this genomic region to non-allelic homologous recombination, which results in deletions, duplications, and the formation of OPN1LW/OPN1MW-hybrid genes (4–6). In the normal human retina, only the most proximal two genes in the cluster are expressed (2). Red or green expression in cone photoreceptors is accomplished by interaction of the gene promoter with a locus control region (LCR), a unique cis-regulatory DNA sequence located ~4 kb upstream of OPN1LW (7). In about 90% of males affected by BCM, Xq28 deletions or point mutations inactivating both OPN1LW and OPN1MW have been identified by polymerase chain reaction (PCR)-based molecular testing, while ~10% of patients have negative results and the molecular defects remain unknown (2, 6), precluding accurate information on disease progression in affected males and female carriers, carrier and prenatal testing, potential approaches, and efficiency of gene therapy. The Xq28 deletions may remove the LCR, inactivating both wild-type opsin genes, or extend into the opsin cluster (4, 6). The complex structure of the LCR and opsin genes, the presence of highly homologous sequences, and variability within the opsin genomic region among human populations pose multiple challenges and limit the effectiveness of diagnostic and carrier testing in families with BCM. Microarray platforms are now used extensively for diagnosis and research to detect genomic imbalances contributing to human disease and population diversity (8, 9). High-resolution microarrays provide distinct benefits in studying males affected with X-linked disorders (9). Single gene alterations are more likely to be present in affected males; however, the resolution of clinical whole-genome microarray platforms, ranging from 25–200 kb, is often insufficient to detect smaller X-chromosome imbalances. We identified novel molecular alterations in three BCM families, using high-resolution X chromosome-targeted (X-HR) array comparative genomic hybridization (aCGH) and report the advantages and limitations of microarray analysis in the diagnosis of BCM and other X-linked conditions.
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High‐resolution microarray analysis unravels complex Xq28 aberrations in patients and carriers affected by X‐linked blue cone monochromacy
Clinical Genetics, 2015Co-Authors: Svetlana A Yatsenko, Barbara J Jennings, Heather A Bakos, Kathleen Vitullo, Marina Kedrov, Archana Kishore, Stephen Cercone, Michelle A. Wood-trageser, Urvashi Surti, Alexander N YatsenkoAbstract:A loss-of-function of both the OPN1LW (red) and OPN1MW (green) cone opsin photopigment genes causes blue cone monochromacy (BCM; OMIM#303700), a rare X-linked, recessive disorder characterized by markedly reduced vision, severe photophobia, congenital nystagmus, and inability to discriminate colors. In humans, up to nine copies of the OPN1LW and OPN1MW genes are arranged in a 5′ −3′ orientation within Xq28, forming the cluster (1–3). The close physical location and high (99.8%) sequence homology predispose this genomic region to non-allelic homologous recombination, which results in deletions, duplications, and the formation of OPN1LW/OPN1MW-hybrid genes (4–6). In the normal human retina, only the most proximal two genes in the cluster are expressed (2). Red or green expression in cone photoreceptors is accomplished by interaction of the gene promoter with a locus control region (LCR), a unique cis-regulatory DNA sequence located ~4 kb upstream of OPN1LW (7). In about 90% of males affected by BCM, Xq28 deletions or point mutations inactivating both OPN1LW and OPN1MW have been identified by polymerase chain reaction (PCR)-based molecular testing, while ~10% of patients have negative results and the molecular defects remain unknown (2, 6), precluding accurate information on disease progression in affected males and female carriers, carrier and prenatal testing, potential approaches, and efficiency of gene therapy. The Xq28 deletions may remove the LCR, inactivating both wild-type opsin genes, or extend into the opsin cluster (4, 6). The complex structure of the LCR and opsin genes, the presence of highly homologous sequences, and variability within the opsin genomic region among human populations pose multiple challenges and limit the effectiveness of diagnostic and carrier testing in families with BCM. Microarray platforms are now used extensively for diagnosis and research to detect genomic imbalances contributing to human disease and population diversity (8, 9). High-resolution microarrays provide distinct benefits in studying males affected with X-linked disorders (9). Single gene alterations are more likely to be present in affected males; however, the resolution of clinical whole-genome microarray platforms, ranging from 25–200 kb, is often insufficient to detect smaller X-chromosome imbalances. We identified novel molecular alterations in three BCM families, using high-resolution X chromosome-targeted (X-HR) array comparative genomic hybridization (aCGH) and report the advantages and limitations of microarray analysis in the diagnosis of BCM and other X-linked conditions.
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High‐resolution microarray analysis unravels complex Xq28 aberrations in patients and carriers affected by X‐linked blue cone monochromacy
Clinical genetics, 2015Co-Authors: Svetlana A Yatsenko, Barbara J Jennings, Heather A Bakos, Kathleen Vitullo, Marina Kedrov, Archana Kishore, Stephen Cercone, Michelle A. Wood-trageser, Urvashi Surti, Alexander N YatsenkoAbstract:The human X chromosome contains ∼ 1600 genes, about 15% of which have been associated with a specific genetic condition, mainly affecting males. Blue cone monochromacy (BCM) is an X-linked condition caused by a loss-of-function of both the OPN1LW and OPN1MW opsin genes. The cone opsin gene cluster is composed of 2-9 paralogs with 99.8% sequence homology and is susceptible to deletions, duplications, and mutations. Current diagnostic tests employ polymerase chain reaction (PCR)-based technologies; however, alterations remain undetermined in 10% of patients. Furthermore, carrier testing in females is limited or unavailable. High-resolution X chromosome-targeted CGH microarray was applied to test for rearrangements in males with BCM and female carriers from three unrelated families. Pathogenic alterations were revealed in all probands, characterized by sequencing of the breakpoint junctions and quantitative real-time PCR. In two families, we identified a novel founder mutation that consisted of a complex 3-kb deletion that embraced the cis-regulatory locus control region and insertion of an additional aberrant OPN1MW gene. The application of high-resolution X-chromosome microarray in clinical diagnosis brings significant advantages in detection of small aberrations that are beyond the resolution of clinically available aCGH analysis and which can improve molecular diagnosis of the known conditions and unravel previously unrecognized X-linked diseases.
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blue cone monochromacy visual function and efficacy outcome measures for clinical trials
PLOS ONE, 2015Co-Authors: Artur V Cideciyan, Alejandro J. Roman, Lauren C Ditta, Barbara J Jennings, Svetlana A Yatsenko, Rebecca Sheplock, Alexander Sumaroka, Malgorzata Swider, Alessandro Iannaccone, Sharon B SchwartzAbstract:Background Blue Cone Monochromacy (BCM) is an X-linked retinopathy caused by mutations in the OPN1LW / OPN1MW gene cluster, encoding long (L)- and middle (M)-wavelength sensitive cone opsins. Recent evidence shows sufficient structural integrity of cone photoreceptors in BCM to warrant consideration of a gene therapy approach to the disease. In the present study, the vision in BCM is examined, specifically seeking clinically-feasible outcomes for a future clinical trial. Methods BCM patients (n = 25, ages 5–72) were studied with kinetic and static chromatic perimetry, full-field sensitivity testing, and eye movement recordings. Vision at the fovea and parafovea was probed with chromatic microperimetry. Results Kinetic fields with a Goldmann size V target were generally full. Short-wavelength (S-) sensitive cone function was normal or near normal in most patients. Light-adapted perimetry results on conventional background lights were abnormally reduced; 600-nm stimuli were seen by rods whereas white stimuli were seen by both rods and S-cones. Under dark-adapted conditions, 500-nm stimuli were seen by rods in both BCM and normals. Spectral sensitivity functions in the superior retina showed retained rod and S-cone functions in BCM under dark-adapted and light-adapted conditions. In the fovea, normal subjects showed L/M-cone mediation using a 650-nm stimulus under dark-adapted conditions, whereas BCM patients had reduced sensitivity driven by rod vision. Full-field red stimuli on bright blue backgrounds were seen by L/M-cones in normal subjects whereas BCM patients had abnormally reduced and rod-mediated sensitivities. Fixation location could vary from fovea to parafovea. Chromatic microperimetry demonstrated a large loss of sensitivity to red stimuli presented on a cyan adapting background at the anatomical fovea and surrounding parafovea. Conclusions BCM rods continue to signal vision under conditions normally associated with daylight vision. Localized and retina-wide outcome measures were examined to evaluate possible improvement of L/M-cone-based vision in a clinical trial.
Artur V Cideciyan - One of the best experts on this subject based on the ideXlab platform.
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Reading Performance in Blue Cone Monochromacy: Defining an Outcome Measure for a Clinical Trial.
Translational vision science & technology, 2020Co-Authors: Evelyn P. Semenov, Alejandro J. Roman, Rebecca Sheplock, Malgorzata Swider, Artur V Cideciyan, David B. Mcguigan, Samuel G JacobsonAbstract:Purpose Blue cone monochromacy (BCM), a congenital X-linked retinal disease caused by mutations in the OPN1LW/OPN1MW gene cluster, is under consideration for intravitreal gene therapy. Difficulties with near vision tasks experienced by these patients prompted this study of reading performance as a potential outcome measure for a future clinical trial. Methods Clinically and molecularly diagnosed patients with BCM (n = 17; ages 15-63 years) and subjects with normal vision (n = 22; ages 18-72 years) were examined with the MNREAD acuity chart for both uniocular and binocular conditions. Parameters derived from the measurements in patients were compared with normal data and also within the group of patients. Intersession, interocular and between-subject variabilities were determined. The frequent complaint of light sensitivity in BCM was examined by comparing results from black text on a white background (regular polarity) versus white on black (reverse polarity) conditions. Results MNREAD curves of print size versus reading speed were right-shifted compared with normal in all patients with BCM. All parameters in patients with BCM indicated abnormal reading performance. Intersession variability was slightly higher in BCM than in normal, but comparable with results previously reported for other patients with maculopathies. There was a high degree of disease symmetry in reading performance in this BCM cohort. Reverse polarity showed better reading parameters than regular polarity in 82% of the patients. Conclusions MNREAD measures of reading performance in patients with BCM would be a worthy and robust secondary outcome in a clinical trial protocol, given its dual purpose of quantifying macular vision and addressing an important quality of life issue. Translational Relevance Assessment of an outcome for a clinical trial.
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foveal therapy in blue cone monochromacy predictions of visual potential from artificial intelligence
Frontiers in Neuroscience, 2020Co-Authors: Alexander Sumaroka, Bernd Wissinger, Rebecca Sheplock, Vivian Wu, Artur V Cideciyan, Susanne Kohl, Samuel G JacobsonAbstract:Novel therapeutic approaches for treating inherited retinal degenerations (IRDs) prompt a need to understand which patients with impaired vision have the anatomical potential to gain from participation in a clinical trial. We used supervised machine learning to predict foveal function from foveal structure in blue cone monochromacy (BCM), an X-linked congenital cone photoreceptor dysfunction secondary to mutations in the OPN1LW/OPN1MW gene cluster. BCM patients with either disease-associated large deletion or missense mutations were studied and results compared with those from subjects with other forms of IRD and various degrees of preserved central structure and function. A machine learning technique was used to associate foveal sensitivities and best-corrected visual acuities to foveal structure in IRD patients. Two random forest models trained on IRD data were applied to predict foveal function in BCM. A curve fitting method was also used and results compared with those of the random forest models. The BCM and IRD patients had a comparable range of foveal structure. IRD patients had peak sensitivity at the fovea. Machine learning could successfully predict foveal sensitivity results from segmented or un-segmented optical coherence tomography input. Application of machine learning predictions to BCM at the fovea showed differences between predicted and measured sensitivities, thereby defining treatment potential. The curve fitting method provided similar results. Given a measure of visual acuity and foveal outer nuclear layer thickness, the question of how many lines of acuity would represent the best efficacious result for each BCM patient could be answered. We propose that foveal vision improvement potential in BCM is predictable from retinal structure using machine learning and curve fitting approaches. This should allow estimates of maximal efficacy in patients being considered for clinical trials and also guide decisions about dosing.
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Foveal Therapy in Blue Cone Monochromacy: Predictions of Visual Potential From Artificial Intelligence.
Frontiers in neuroscience, 2020Co-Authors: Alexander Sumaroka, Bernd Wissinger, Rebecca Sheplock, Artur V Cideciyan, Susanne Kohl, Samuel G JacobsonAbstract:Novel therapeutic approaches for treating inherited retinal degenerations (IRDs) prompt a need to understand which patients with impaired vision have the anatomical potential to gain from participation in a clinical trial. We used supervised machine learning to predict foveal function from foveal structure in blue cone monochromacy (BCM), an X-linked congenital cone photoreceptor dysfunction secondary to mutations in the OPN1LW/OPN1MW gene cluster. BCM patients with either disease-associated large deletion or missense mutations were studied and results compared with those from subjects with other forms of IRD and various degrees of preserved central structure and function. A machine learning technique was used to associate foveal sensitivities and best-corrected visual acuities to foveal structure in IRD patients. Two random forest (RF) models trained on IRD data were applied to predict foveal function in BCM. A curve fitting method was also used and results compared with those of the RF models. The BCM and IRD patients had a comparable range of foveal structure. IRD patients had peak sensitivity at the fovea. Machine learning could successfully predict foveal sensitivity (FS) results from segmented or un-segmented optical coherence tomography (OCT) input. Application of machine learning predictions to BCM at the fovea showed differences between predicted and measured sensitivities, thereby defining treatment potential. The curve fitting method provided similar results. Given a measure of visual acuity (VA) and foveal outer nuclear layer thickness, the question of how many lines of acuity would represent the best efficacious result for each BCM patient could be answered. We propose that foveal vision improvement potential in BCM is predictable from retinal structure using machine learning and curve fitting approaches. This should allow estimates of maximal efficacy in patients being considered for clinical trials and also guide decisions about dosing.
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blue cone monochromacy visual function and efficacy outcome measures for clinical trials
PLOS ONE, 2015Co-Authors: Artur V Cideciyan, Alejandro J. Roman, Lauren C Ditta, Barbara J Jennings, Svetlana A Yatsenko, Rebecca Sheplock, Alexander Sumaroka, Malgorzata Swider, Alessandro Iannaccone, Sharon B SchwartzAbstract:Background Blue Cone Monochromacy (BCM) is an X-linked retinopathy caused by mutations in the OPN1LW / OPN1MW gene cluster, encoding long (L)- and middle (M)-wavelength sensitive cone opsins. Recent evidence shows sufficient structural integrity of cone photoreceptors in BCM to warrant consideration of a gene therapy approach to the disease. In the present study, the vision in BCM is examined, specifically seeking clinically-feasible outcomes for a future clinical trial. Methods BCM patients (n = 25, ages 5–72) were studied with kinetic and static chromatic perimetry, full-field sensitivity testing, and eye movement recordings. Vision at the fovea and parafovea was probed with chromatic microperimetry. Results Kinetic fields with a Goldmann size V target were generally full. Short-wavelength (S-) sensitive cone function was normal or near normal in most patients. Light-adapted perimetry results on conventional background lights were abnormally reduced; 600-nm stimuli were seen by rods whereas white stimuli were seen by both rods and S-cones. Under dark-adapted conditions, 500-nm stimuli were seen by rods in both BCM and normals. Spectral sensitivity functions in the superior retina showed retained rod and S-cone functions in BCM under dark-adapted and light-adapted conditions. In the fovea, normal subjects showed L/M-cone mediation using a 650-nm stimulus under dark-adapted conditions, whereas BCM patients had reduced sensitivity driven by rod vision. Full-field red stimuli on bright blue backgrounds were seen by L/M-cones in normal subjects whereas BCM patients had abnormally reduced and rod-mediated sensitivities. Fixation location could vary from fovea to parafovea. Chromatic microperimetry demonstrated a large loss of sensitivity to red stimuli presented on a cyan adapting background at the anatomical fovea and surrounding parafovea. Conclusions BCM rods continue to signal vision under conditions normally associated with daylight vision. Localized and retina-wide outcome measures were examined to evaluate possible improvement of L/M-cone-based vision in a clinical trial.
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Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy.
Human Gene Therapy, 2013Co-Authors: Artur V Cideciyan, Michel Michaelides, Alexander Sumaroka, Megan E. Land, Sharon B Schwartz, Robert B Hufnagel, Alfredo Dubra, Joseph Carroll, Jessica C GardnerAbstract:Human X-linked blue-cone monochromacy (BCM), a disabling congenital visual disorder of cone photoreceptors, is a candidate disease for gene augmentation therapy. BCM is caused by either mutations in the red (OPN1LW) and green (OPN1MW) cone photoreceptor opsin gene array or large deletions encompassing portions of the gene array and upstream regulatory sequences that would predict a lack of red or green opsin expression. The fate of opsin-deficient cone cells is unknown. We know that rod opsin null mutant mice show rapid postnatal death of rod photoreceptors. Using in vivo histology with high-resolution retinal imaging, we studied a cohort of 20 BCM patients (age range 5–58) with large deletions in the red/green opsin gene array. Already in the first years of life, retinal structure was not normal: there was partial loss of photoreceptors across the central retina. Remaining cone cells had detectable outer segments that were abnormally shortened. Adaptive optics imaging confirmed the existence of inner segments at a spatial density greater than that expected for the residual blue cones. The evidence indicates that human cones in patients with deletions in the red/green opsin gene array can survive in reduced numbers with limited outer segment material, suggesting potential value of gene therapy for BCM.
Barbara J Jennings - One of the best experts on this subject based on the ideXlab platform.
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high resolution microarray analysis unravels complex xq28 aberrations in patients and carriers affected by x linked blue cone monochromacy
Clinical Genetics, 2016Co-Authors: Svetlana A Yatsenko, Barbara J Jennings, Heather A Bakos, Kathleen Vitullo, Marina Kedrov, Archana Kishore, Michelle A Woodtrageser, Stephen Cercone, Urvashi Surti, Alexander N YatsenkoAbstract:A loss-of-function of both the OPN1LW (red) and OPN1MW (green) cone opsin photopigment genes causes blue cone monochromacy (BCM; OMIM#303700), a rare X-linked, recessive disorder characterized by markedly reduced vision, severe photophobia, congenital nystagmus, and inability to discriminate colors. In humans, up to nine copies of the OPN1LW and OPN1MW genes are arranged in a 5′ −3′ orientation within Xq28, forming the cluster (1–3). The close physical location and high (99.8%) sequence homology predispose this genomic region to non-allelic homologous recombination, which results in deletions, duplications, and the formation of OPN1LW/OPN1MW-hybrid genes (4–6). In the normal human retina, only the most proximal two genes in the cluster are expressed (2). Red or green expression in cone photoreceptors is accomplished by interaction of the gene promoter with a locus control region (LCR), a unique cis-regulatory DNA sequence located ~4 kb upstream of OPN1LW (7). In about 90% of males affected by BCM, Xq28 deletions or point mutations inactivating both OPN1LW and OPN1MW have been identified by polymerase chain reaction (PCR)-based molecular testing, while ~10% of patients have negative results and the molecular defects remain unknown (2, 6), precluding accurate information on disease progression in affected males and female carriers, carrier and prenatal testing, potential approaches, and efficiency of gene therapy. The Xq28 deletions may remove the LCR, inactivating both wild-type opsin genes, or extend into the opsin cluster (4, 6). The complex structure of the LCR and opsin genes, the presence of highly homologous sequences, and variability within the opsin genomic region among human populations pose multiple challenges and limit the effectiveness of diagnostic and carrier testing in families with BCM. Microarray platforms are now used extensively for diagnosis and research to detect genomic imbalances contributing to human disease and population diversity (8, 9). High-resolution microarrays provide distinct benefits in studying males affected with X-linked disorders (9). Single gene alterations are more likely to be present in affected males; however, the resolution of clinical whole-genome microarray platforms, ranging from 25–200 kb, is often insufficient to detect smaller X-chromosome imbalances. We identified novel molecular alterations in three BCM families, using high-resolution X chromosome-targeted (X-HR) array comparative genomic hybridization (aCGH) and report the advantages and limitations of microarray analysis in the diagnosis of BCM and other X-linked conditions.
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High‐resolution microarray analysis unravels complex Xq28 aberrations in patients and carriers affected by X‐linked blue cone monochromacy
Clinical Genetics, 2015Co-Authors: Svetlana A Yatsenko, Barbara J Jennings, Heather A Bakos, Kathleen Vitullo, Marina Kedrov, Archana Kishore, Stephen Cercone, Michelle A. Wood-trageser, Urvashi Surti, Alexander N YatsenkoAbstract:A loss-of-function of both the OPN1LW (red) and OPN1MW (green) cone opsin photopigment genes causes blue cone monochromacy (BCM; OMIM#303700), a rare X-linked, recessive disorder characterized by markedly reduced vision, severe photophobia, congenital nystagmus, and inability to discriminate colors. In humans, up to nine copies of the OPN1LW and OPN1MW genes are arranged in a 5′ −3′ orientation within Xq28, forming the cluster (1–3). The close physical location and high (99.8%) sequence homology predispose this genomic region to non-allelic homologous recombination, which results in deletions, duplications, and the formation of OPN1LW/OPN1MW-hybrid genes (4–6). In the normal human retina, only the most proximal two genes in the cluster are expressed (2). Red or green expression in cone photoreceptors is accomplished by interaction of the gene promoter with a locus control region (LCR), a unique cis-regulatory DNA sequence located ~4 kb upstream of OPN1LW (7). In about 90% of males affected by BCM, Xq28 deletions or point mutations inactivating both OPN1LW and OPN1MW have been identified by polymerase chain reaction (PCR)-based molecular testing, while ~10% of patients have negative results and the molecular defects remain unknown (2, 6), precluding accurate information on disease progression in affected males and female carriers, carrier and prenatal testing, potential approaches, and efficiency of gene therapy. The Xq28 deletions may remove the LCR, inactivating both wild-type opsin genes, or extend into the opsin cluster (4, 6). The complex structure of the LCR and opsin genes, the presence of highly homologous sequences, and variability within the opsin genomic region among human populations pose multiple challenges and limit the effectiveness of diagnostic and carrier testing in families with BCM. Microarray platforms are now used extensively for diagnosis and research to detect genomic imbalances contributing to human disease and population diversity (8, 9). High-resolution microarrays provide distinct benefits in studying males affected with X-linked disorders (9). Single gene alterations are more likely to be present in affected males; however, the resolution of clinical whole-genome microarray platforms, ranging from 25–200 kb, is often insufficient to detect smaller X-chromosome imbalances. We identified novel molecular alterations in three BCM families, using high-resolution X chromosome-targeted (X-HR) array comparative genomic hybridization (aCGH) and report the advantages and limitations of microarray analysis in the diagnosis of BCM and other X-linked conditions.
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High‐resolution microarray analysis unravels complex Xq28 aberrations in patients and carriers affected by X‐linked blue cone monochromacy
Clinical genetics, 2015Co-Authors: Svetlana A Yatsenko, Barbara J Jennings, Heather A Bakos, Kathleen Vitullo, Marina Kedrov, Archana Kishore, Stephen Cercone, Michelle A. Wood-trageser, Urvashi Surti, Alexander N YatsenkoAbstract:The human X chromosome contains ∼ 1600 genes, about 15% of which have been associated with a specific genetic condition, mainly affecting males. Blue cone monochromacy (BCM) is an X-linked condition caused by a loss-of-function of both the OPN1LW and OPN1MW opsin genes. The cone opsin gene cluster is composed of 2-9 paralogs with 99.8% sequence homology and is susceptible to deletions, duplications, and mutations. Current diagnostic tests employ polymerase chain reaction (PCR)-based technologies; however, alterations remain undetermined in 10% of patients. Furthermore, carrier testing in females is limited or unavailable. High-resolution X chromosome-targeted CGH microarray was applied to test for rearrangements in males with BCM and female carriers from three unrelated families. Pathogenic alterations were revealed in all probands, characterized by sequencing of the breakpoint junctions and quantitative real-time PCR. In two families, we identified a novel founder mutation that consisted of a complex 3-kb deletion that embraced the cis-regulatory locus control region and insertion of an additional aberrant OPN1MW gene. The application of high-resolution X-chromosome microarray in clinical diagnosis brings significant advantages in detection of small aberrations that are beyond the resolution of clinically available aCGH analysis and which can improve molecular diagnosis of the known conditions and unravel previously unrecognized X-linked diseases.
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blue cone monochromacy visual function and efficacy outcome measures for clinical trials
PLOS ONE, 2015Co-Authors: Artur V Cideciyan, Alejandro J. Roman, Lauren C Ditta, Barbara J Jennings, Svetlana A Yatsenko, Rebecca Sheplock, Alexander Sumaroka, Malgorzata Swider, Alessandro Iannaccone, Sharon B SchwartzAbstract:Background Blue Cone Monochromacy (BCM) is an X-linked retinopathy caused by mutations in the OPN1LW / OPN1MW gene cluster, encoding long (L)- and middle (M)-wavelength sensitive cone opsins. Recent evidence shows sufficient structural integrity of cone photoreceptors in BCM to warrant consideration of a gene therapy approach to the disease. In the present study, the vision in BCM is examined, specifically seeking clinically-feasible outcomes for a future clinical trial. Methods BCM patients (n = 25, ages 5–72) were studied with kinetic and static chromatic perimetry, full-field sensitivity testing, and eye movement recordings. Vision at the fovea and parafovea was probed with chromatic microperimetry. Results Kinetic fields with a Goldmann size V target were generally full. Short-wavelength (S-) sensitive cone function was normal or near normal in most patients. Light-adapted perimetry results on conventional background lights were abnormally reduced; 600-nm stimuli were seen by rods whereas white stimuli were seen by both rods and S-cones. Under dark-adapted conditions, 500-nm stimuli were seen by rods in both BCM and normals. Spectral sensitivity functions in the superior retina showed retained rod and S-cone functions in BCM under dark-adapted and light-adapted conditions. In the fovea, normal subjects showed L/M-cone mediation using a 650-nm stimulus under dark-adapted conditions, whereas BCM patients had reduced sensitivity driven by rod vision. Full-field red stimuli on bright blue backgrounds were seen by L/M-cones in normal subjects whereas BCM patients had abnormally reduced and rod-mediated sensitivities. Fixation location could vary from fovea to parafovea. Chromatic microperimetry demonstrated a large loss of sensitivity to red stimuli presented on a cyan adapting background at the anatomical fovea and surrounding parafovea. Conclusions BCM rods continue to signal vision under conditions normally associated with daylight vision. Localized and retina-wide outcome measures were examined to evaluate possible improvement of L/M-cone-based vision in a clinical trial.