Publications by authors named "Bart P Leroy"

122 Publications

Durability of Voretigene Neparvovec for Biallelic RPE65-Mediated Inherited Retinal Disease: Phase 3 Results at 3 Years and 4 Years.

Ophthalmology 2021 Mar 30. Epub 2021 Mar 30.

Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Cellular and Molecular Therapeutics, Inc., Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Objective: To determine whether functional vision and visual function improvements after voretigene neparvovec (VN; LUXTURNA®, Spark Therapeutics, Inc.) administration in subjects with biallelic RPE65 mutation-associated inherited retinal disease are maintained at 3-4 years, and to review safety outcomes.

Design: Open-label, randomized, controlled phase 3 trial.

Subjects: Thirty-one individuals were enrolled and randomized 2:1 to intervention (n=21) or control (n=10). One subject from each group withdrew before, or at, randomization.

Methods: Subjects in the original intervention (OI) group received bilateral subretinal VN injections. Delayed intervention (DI) subjects served as controls for 1 year, then received VN.

Main Outcome Measures: Change from injection baseline in bilateral performance on the multi-luminance mobility test (MLMT), a measure of ambulatory navigation, and change from injection baseline in full-field light sensitivity threshold (FST) white light, visual field (VF), and visual acuity (VA).

Results: Mean bilateral MLMT change scores at Year 4 for OI subjects and at Year 3 for DI subjects were 1.7 and 2.4 respectively, with 71% of subjects with a Year 3 visit able to pass MLMT at the lowest light level. Mean change in FST white light, averaged over both eyes at Year 4 for OI subjects, and at Year 3 for DI subjects, was -1.90 log(cd.s/m) and -2.91 log(cd.s/m), respectively. Mean change in Goldmann kinetic VF III4e sum total degrees, averaged across both eyes, was 197.7 at Year 4 for OI subjects and 157.9 at Year 3 for DI subjects. Mean change in VA (Holladay scale), averaged across both eyes, was -0.003 logMAR at Year 4 for OI subjects and -0.06 logMAR at Year 3 for DI subjects. One OI subject had a retinal detachment around Year 4, which impacted VA for the OI group. No product-related serious adverse events (SAEs) occurred, and there were no deleterious immune responses.

Conclusions: Improvements in ambulatory navigation, light sensitivity, and VF were consistent in both intervention groups. Overall, improvements were maintained up to 3-4 years, with ongoing observation. The safety profile of VN was consistent with vitrectomy and the subretinal injection procedure, and was similar between intervention groups, with no product-related SAEs reported.
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http://dx.doi.org/10.1016/j.ophtha.2021.03.031DOI Listing
March 2021

The need for widely available genomic testing in rare eye diseases: an ERN-EYE position statement.

Orphanet J Rare Dis 2021 Mar 20;16(1):142. Epub 2021 Mar 20.

ERN-EYE Coordination Center, Hopitaux Universitaires de Strasbourg, Strasbourg, France.

Background: Rare Eye Diseases (RED) are the leading cause of visual impairment and blindness for children and young adults in Europe. This heterogeneous group of conditions includes over 900 disorders ranging from relatively prevalent disorders such as retinitis pigmentosa to very rare entities such as developmental eye anomalies. A significant number of patients with RED have an underlying genetic etiology. One of the aims of the European Reference Network for Rare Eye Diseases (ERN-EYE) is to facilitate improvement in diagnosis of RED in European member states.

Main Body: Technological advances have allowed genetic and genomic testing for RED. The outcome of genetic testing allows better understanding of the condition and allows reproductive and therapeutic options. The increase of the number of clinical trials for RED has provided urgency for genetic testing in RED. A survey of countries participating in ERN-EYE demonstrated that the majority are able to access some forms of genomic testing. However, there is significant variability, particularly regarding testing as part of clinical service. Some countries have a well-delineated rare disease pathway and have a national plan for rare diseases combined or not with a national plan for genomics in medicine. In other countries, there is a well-established organization of genetic centres that offer reimbursed genomic testing of RED and other rare diseases. Clinicians often rely upon research-funded laboratories or private companies. Notably, some member states rely on cross-border testing by way of an academic research project. Consequently, many clinicians are either unable to access testing or are confronted with long turnaround times. Overall, while the cost of sequencing has dropped, the cumulative cost of a genomic testing service for populations remains considerable. Importantly, the majority of countries reported healthcare budgets that limit testing.

Short Conclusion: Despite technological advances, critical gaps in genomic testing remain in Europe, especially in smaller countries where no formal genomic testing pathways exist. Even within larger countries, the existing arrangements are insufficient to meet the demand and to ensure access. ERN-EYE promotes access to genetic testing in RED and emphasizes the clinical need and relevance of genetic testing in RED.
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http://dx.doi.org/10.1186/s13023-021-01756-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980559PMC
March 2021

A Virtual Reality Orientation and Mobility Test for Inherited Retinal Degenerations: Testing a Proof-of-Concept After Gene Therapy.

Clin Ophthalmol 2021 2;15:939-952. Epub 2021 Mar 2.

Scheie Eye Institute at the Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: To test the ability of a virtual reality (VR) orientation and mobility (O&M) protocol to serve a measure of functional vision for patients with inherited retinal degenerations (IRDs).

Methods: A VR-O&M protocol designed using a commercially available VR hardware was tested in normally sighted control subjects (n=7; ages 10-35yo; Average 22.5yo) and patients with -associated Leber Congenital Amaurosis (n=3; ages 7-18yo; Average 12.7yo), in two of them before and after gene therapy. Patients underwent perimetry and full-field sensitivity testing. VR-O&M parameters correlated with the visual dysfunction.

Results: Visual acuities in patients were on average worse than 20/200, dark-adapted sensitivity losses >5 log units, and fields constricted between 20° and 40°. Before treatment, patients required ~1000-fold brighter environment to navigate, had at least x4 more collisions, and were slower both to orient and navigate compared to control subjects. Improvements in cone- (by 1-2 L.u.) and rod-mediated (by >4 L.u.) sensitivities post-treatment led to fewer collisions (at least by half) at ~100-fold dimmer luminances, and to x4 times faster navigation times.

Conclusion: This study provides proof-of-concept data in support for the use of VR-O&M systems to quantify the impact that the visual dysfunction and improvement of vision following treatments has on functional vision in IRDs. The VR-O&M was useful in potentially challenging scenarios such as in pediatric patients with severe IRDs.

Translational Relevance: A VR-O&M test will provide much needed flexibility, both in its deployment as well as in the possibility to test various attributes of vision that may be impacted by gene therapy in the setting of translational studies.

Precis: This study provides proof-of-concept data in support for the use of a virtual reality orientation and mobility test to quantify the impact of the disease and of treatments thereof on functional vision in inherited retinal degenerations.
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http://dx.doi.org/10.2147/OPTH.S292527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936670PMC
March 2021

Leber Congenital Amaurosis Due to CEP290 Mutations - Severe Vision Impairment with a High Unmet Medical Need: A Review.

Retina 2021 Feb 1. Epub 2021 Feb 1.

Department of Ophthalmology Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium Division of Ophthalmology Center for Cellular & Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Retina Foundation of the Southwest, Dallas, TX, USA Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA Departments of Paediatric Surgery, Human Genetics, and Adult Ophthalmology, McGill University Health Center, Montreal, Quebec, Canada INRET Clínica e Centro de Pesquisa, Belo Horizonte, Brazil The University of Iowa Institute for Vision Research, University of Iowa, Iowa City, IA, USA ProQR Therapeutics, Leiden, the Netherlands.

Purpose: Leber congenital amaurosis due to CEP290 mutations (LCA10) is an inherited retinal disease that often results in severe visual impairment or blindness in early childhood. Currently there are no approved treatments, highlighting the considerable unmet medical need associated with LCA10. We aimed to review the clinical characteristics of LCA10, its impact on patients and society, and the investigational treatment strategies currently in development.

Methods: Review of the current literature.

Results: LCA10 is an autosomal recessive ciliopathy, for which the CEP290 intronic variant c.2991+1655A>G (p.Cys998X) is the most common mutation. Usually diagnosed in early childhood, most patients with LCA10 have severe visual impairment during their first decade of life, which significantly affects quality of life and development. LCA10 also has a significant societal burden (direct and indirect costs). RNA editing using antisense oligonucleotides (AONs) or Staphylococcus aureus CRISPR-associated protein-9 nuclease are currently under investigation for treatment of p.Cys998X LCA10. Specifically, the AON therapy QR-110 (sepofarsen) has demonstrated encouraging safety and efficacy data in a first-in-human trial; a phase 3 clinical trial is ongoing.

Conclusions: Interventions that can preserve or improve vision in patients with LCA10 have considerable potential to improve patient quality of life and reduce burden of disease.
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http://dx.doi.org/10.1097/IAE.0000000000003133DOI Listing
February 2021

Phenocopy of a heterozygous carrier of X-linked retinitis pigmentosa due to mosaicism for a RHO variant.

Sci Rep 2021 Jan 8;11(1):117. Epub 2021 Jan 8.

Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.

We describe both phenotype and pathogenesis in two male siblings with typical retinitis pigmentosa (RP) and the potentially X-linked RP (XLRP) carrier phenotype in their mother. Two affected sons, two unaffected daughters, and their mother underwent detailed ophthalmological assessments including Goldmann perimetry, color vision testing, multimodal imaging and ISCEV-standard electroretinography. Genetic testing consisted of targeted next-generation sequencing (NGS) of known XLRP genes and whole exome sequencing (WES) of known inherited retinal disease genes (RetNet-WES). Variant validation and segregation analysis were performed by Sanger sequencing. The mutational load of the RHO variant in the mother was assessed in DNA from leucocytes, buccal cells and hair follicles using targeted NGS. Both affected sons showed signs of classical RP, while the mother displayed patches of hyperautofluorescence on blue light autofluorescence imaging and regional, intraretinal, spicular pigmentation, reminiscent of a carrier phenotype of XLRP. XLRP testing was negative. RetNet-WES testing revealed RHO variant c.404G > C p.(Arg135Pro) in a mosaic state (21% of the reads) in the mother and in a heterozygous state in both sons. Targeted NGQSS of the RHO variant in different maternal tissues showed a mutation load between 25.06% and 41.72%. We report for the first time that somatic mosaicism of RHO variant c.404G > C p.(Arg135Pro) mimics the phenotype of a female carrier of XLRP, in combination with heterozygosity for the variant in the two affected sons.
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http://dx.doi.org/10.1038/s41598-020-80400-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794345PMC
January 2021

Clinical Perspective: Treating RPE65-Associated Retinal Dystrophy.

Mol Ther 2021 02 3;29(2):442-463. Epub 2020 Dec 3.

Center for Advanced Retinal and Ocular Therapeutics (CAROT), Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; The Children's Hospital of Philadelphia (CHOP), Philadelphia, PA, USA. Electronic address:

Until recently, there was no approved treatment for a retinal degenerative disease. Subretinal injection of a recombinant adeno-associated virus (AAV) delivering the normal copy of the human RPE65 cDNA led to reversal of blindness first in animal models and then in humans. This led to the first US Food and Drug Administration (FDA)-approved gene therapy product for a genetic disease, voretigene neparvovec-rzyl (Luxturna). Luxturna was then approved by the European Medicines Association and is now available in the US through Spark Therapeutics and worldwide through Novartis. Not only has treatment with Luxturna changed the lives of people previously destined to live a life of blindness, but it has fueled interest in developing additional gene therapy reagents targeting numerous other genetic forms of inherited retinal disease. This review describes many of the considerations for administration of Luxturna and describes how lessons from experience with Luxturna could lead to additional gene-based treatments of blindness.
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http://dx.doi.org/10.1016/j.ymthe.2020.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854308PMC
February 2021

New variants and in silico analyses in GRK1 associated Oguchi disease.

Hum Mutat 2021 Feb 30;42(2):164-176. Epub 2020 Nov 30.

Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds, UK.

Biallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify disease causing GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients' genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function in-silico.
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http://dx.doi.org/10.1002/humu.24140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898643PMC
February 2021

Vitreous Hemorrhage as Presenting Sign of Retinal Arteriovenous Malformation.

Case Rep Ophthalmol Med 2020 19;2020:8858242. Epub 2020 Oct 19.

Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.

Objective: To describe a patient with vitreous hemorrhage and peripheral retinal ischemia, eventually diagnosed with an underlying retinal arteriovenous malformation.

Methods: A 15-year-old girl presented with sudden-onset, painless visual loss in the right eye. She underwent a full ophthalmological work-up.

Results: BCVA was less than 20/400 in the right eye and 20/20 in the left eye. Intraocular pressure and anterior segment examination were unremarkable. Fundoscopy was impossible due to an opaque vitreous hemorrhage in the right eye. The left eye was completely unremarkable. Examination during a 23-gauge pars plana vitrectomy showed dilated, tortuous arteriovenous vessels extending from the optic disc and silver wiring of the enlarged vessels. A clinical diagnosis of retinal arteriovenous malformation was made. During surgery, a peripheral retinal photocoagulation was executed to avoid rebleeding. Postoperatively, fluorescein angiography demonstrated additional macular microangiopathy and diffuse retinal nonperfusion in the periphery. The MRI brain revealed neither cerebral nor orbital vascular anomaly, confirming a group 2 retinal arteriovenous malformation.

Conclusion: Retinal arteriovenous malformations are generally considered stable over time. However, complications due to retinal ischemia can occur. Hence, regular observation is warranted. In so doing, timely treatment can be offered to avoid complications.
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http://dx.doi.org/10.1155/2020/8858242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591971PMC
October 2020

Clinical Phenotype and Course of PDE6A-Associated Retinitis Pigmentosa Disease, Characterized in Preparation for a Gene Supplementation Trial.

JAMA Ophthalmol 2020 Oct 15. Epub 2020 Oct 15.

Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University Tübingen, Tübingen, Germany.

Importance: Treatment trials require sound knowledge on the natural course of disease.

Objective: To assess clinical features, genetic findings, and genotype-phenotype correlations in patients with retinitis pigmentosa (RP) associated with biallelic sequence variations in the PDE6A gene in preparation for a gene supplementation trial.

Design, Setting, And Participants: This prospective, longitudinal, observational cohort study was conducted from January 2001 to December 2019 in a single center (Centre for Ophthalmology of the University of Tübingen, Germany) with patients recruited multinationally from 12 collaborating European tertiary referral centers. Patients with retinitis pigmentosa, sequence variants in PDE6A, and the ability to provide informed consent were included.

Exposures: Comprehensive ophthalmological examinations; validation of compound heterozygosity and biallelism by familial segregation analysis, allelic cloning, or assessment of next-generation sequencing-read data, where possible.

Main Outcomes And Measures: Genetic findings and clinical features describing the entire cohort and comparing patients harboring the 2 most common disease-causing variants in a homozygous state (c.304C>A;p.(R102S) and c.998 + 1G>A;p.?).

Results: Fifty-seven patients (32 female patients [56%]; mean [SD], 40 [14] years) from 44 families were included. All patients completed the study. Thirty patients were homozygous for disease-causing alleles. Twenty-seven patients were heterozygous for 2 different PDE6A variants each. The most frequently observed alleles were c.304C>A;p.(R102S), c.998 + 1G>A;p.?, and c.2053G>A;p.(V685M). The mean (SD) best-corrected visual acuity was 0.43 (0.48) logMAR (Snellen equivalent, 20/50). The median visual field area with object III4e was 660 square degrees (5th and 95th percentiles, 76 and 11 019 square degrees; 25th and 75th percentiles, 255 and 3923 square degrees). Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%). Sixty-nine of 108 eyes (62.9%) showed additional findings on optical coherence tomography imaging (eg, cystoid macular edema or macular atrophy). The variant c.998 + 1G>A;p.? led to a more severe phenotype when compared with the variant c.304C>A;p.(R102S).

Conclusions And Relevance: Seventeen of the PDE6A variants found in these patients appeared to be novel. Regarding the clinical findings, disease was highly symmetrical between the right and left eyes and visual impairment was mild or moderate in 90% of patients, providing a window of opportunity for gene therapy.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.4206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563671PMC
October 2020

The corneoscleral shape in Marfan syndrome.

Acta Ophthalmol 2020 Sep 30. Epub 2020 Sep 30.

Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.

Purpose: To investigate the corneoscleral shape in Marfan syndrome (MFS) patients.

Methods: Thirty eyes of 15 participants with molecularly proven MFS were included in this prospective, cross-sectional study. Optical biometry, Scheimpflug imaging, and corneoscleral topography (Eye Surface Profiler) were performed in all patients. Topographic data were compared to data from controls (25 emmetropes and 17 myopes). The raw three-dimensional anterior height data from MFS eyes and control eyes were exported for further analysis. Custom-made software was used to demarcate the limbal radius and to calculate the sagittal height in different concentric annuli centred at the corneal apex, placed in a pupil plane, for the central cornea (0-4 mm radius), peripheral cornea (4-6 mm radius) and sclera (6-8 mm radius) and the corneoscleral asymmetry.

Results: Marfan syndrome (MFS) eyes had significantly lower values of mean sagittal height compared to non-MFS eyes in all three annuli (central cornea, corneal periphery and sclera (independent t-test, p < 0.01 except for the inferior area of the scleral radius: p > 0.05). The sclera was significantly more asymmetric in MFS eyes compared to myopes (independent t-test, p < 0.01 for both eyes), but similar to emmetropes (independent t-test, p = 0.17 and p = 0.93 for right and left eyes, respectively). In MFS eyes, scleral asymmetry was not found to be correlated with axial length (Pearson correlation coefficient, r < 0.30, p > 0.05).

Conclusion: The peripheral cornea and sclera of Marfan syndrome patients have a significantly different shape compared to healthy controls.
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http://dx.doi.org/10.1111/aos.14636DOI Listing
September 2020

Advancing Clinical Trials for Inherited Retinal Diseases: Recommendations from the Second Monaciano Symposium.

Transl Vis Sci Technol 2020 06 3;9(7). Epub 2020 Jun 3.

Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA.

Major advances in the study of inherited retinal diseases (IRDs) have placed efforts to develop treatments for these blinding conditions at the forefront of the emerging field of precision medicine. As a result, the growth of clinical trials for IRDs has increased rapidly over the past decade and is expected to further accelerate as more therapeutic possibilities emerge and qualified participants are identified. Although guided by established principles, these specialized trials, requiring analysis of novel outcome measures and endpoints in small patient populations, present multiple challenges relative to study design and ethical considerations. This position paper reviews recent accomplishments and existing challenges in clinical trials for IRDs and presents a set of recommendations aimed at rapidly advancing future progress. The goal is to stimulate discussions among researchers, funding agencies, industry, and policy makers that will further the design, conduct, and analysis of clinical trials needed to accelerate the approval of effective treatments for IRDs, while promoting advocacy and ensuring patient safety.
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http://dx.doi.org/10.1167/tvst.9.7.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414644PMC
June 2020

Hydroxychloroquine hitting the headlines-retinal considerations.

Eye (Lond) 2020 07 19;34(7):1158-1160. Epub 2020 May 19.

University Hospitals of Strasbourg, Strasbourg, France.

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http://dx.doi.org/10.1038/s41433-020-0934-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236652PMC
July 2020

CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA: A Long-Term Follow-Up Study.

Retina 2021 Jan;41(1):213-223

Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: To investigate the natural history of RHO-associated retinitis pigmentosa (RP).

Methods: A multicenter, medical chart review of 100 patients with autosomal dominant RHO-associated RP.

Results: Based on visual fields, time-to-event analysis revealed median ages of 52 and 79 years to reach low vision (central visual field <20°) and blindness (central visual field <10°), respectively. For the best-corrected visual acuity (BCVA), the median age to reach mild impairment (20/67 ≤ BCVA < 20/40) was 72 years, whereas this could not be computed for lower acuities. Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%), in terms of decline rates of the BCVA (P < 0.001) and V4e retinal seeing areas (P < 0.005). The foveal thickness of the photoreceptor-retinal pigment epithelium (PR + RPE) complex correlated significantly with BCVA (Spearman's ρ = 0.733; P < 0.001).

Conclusion: Based on central visual fields, the optimal window of intervention for RHO-associated RP is before the 5th decade of life. Significant differences in disease progression are present between generalized and sector RP phenotypes. Our findings suggest that the PR + RPE complex is a potential surrogate endpoint for the BCVA in future studies.
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http://dx.doi.org/10.1097/IAE.0000000000002808DOI Listing
January 2021

VEGFA variants as prognostic markers for the retinopathy in pseudoxanthoma elasticum.

Clin Genet 2020 07 10;98(1):74-79. Epub 2020 May 10.

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive ectopic mineralization disorder, characterized by skin, eye and cardiovascular symptoms. The most devastating ocular complication is choroidal neovascularization, which is thought to be mediated by vascular endothelial growth factor (VEGF) signaling, a molecule encoded by the VEGFA gene. As early detection and treatment is essential to preserve vision, prioritization of patients at risk is crucial, but impossible because of wide phenotypic variability and a lack of genotype-phenotype correlations for PXE. This study aimed to validate the previously suggested association of five single nucleotide VEGFA variants (rs13207351, rs833061, rs699947, rs25648 and rs1413711) with a severe PXE retinopathy in an independent cohort. Direct Sanger sequencing was performed in 100 PXE patients, with a mild (56) or severe (44) PXE retinopathy. The inclusion criteria for severe retinopathy were a unilateral best-corrected visual acuity of <5/10 and/or the need for anti-angiogenic treatment. We found a significant association of three of five variants and borderline missed significance for one. These data further suggest the VEGFA gene to be a modifier gene for the PXE retinopathy. Hereby, we provide the necessary evidence to implement these variants in ocular risk stratification and individualized patient follow-up.
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http://dx.doi.org/10.1111/cge.13751DOI Listing
July 2020

Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility.

Hum Mutat 2020 05 12;41(5):998-1011. Epub 2020 Feb 12.

Department of Biomolecular Medicine, Center for Medical Genetics Ghent, Ghent University Hospital, Ghent University, Ghent, Belgium.

Inactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state-in trans with c.1462-1G>T-in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities.
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http://dx.doi.org/10.1002/humu.23993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187288PMC
May 2020

The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56.

Sci Rep 2020 Jan 28;10(1):1289. Epub 2020 Jan 28.

Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

This study aimed to genetically and clinically characterize a unique cohort of 25 individuals from 21 unrelated families with autosomal recessive nanophthalmos (NNO) and posterior microphthalmia (MCOP) from different ethnicities. An ophthalmological assessment in all families was followed by targeted MFRP and PRSS56 testing in 20 families and whole-genome sequencing in one family. Three families underwent homozygosity mapping using SNP arrays. Eight distinct MFRP mutations were found in 10/21 families (47.6%), five of which are novel including a deletion spanning the 5' untranslated region and the first coding part of exon 1. Most cases harbored homozygous mutations (8/10), while a compound heterozygous and a monoallelic genotype were identified in the remaining ones (2/10). Six distinct PRSS56 mutations were found in 9/21 (42.9%) families, three of which are novel. Similarly, homozygous mutations were found in all but one, leaving 2/21 families (9.5%) without a molecular diagnosis. Clinically, all patients had reduced visual acuity, hyperopia, short axial length and crowded optic discs. Retinitis pigmentosa was observed in 5/10 (50%) of the MFRP group, papillomacular folds in 12/19 (63.2%) of MCOP and in 3/6 (50%) of NNO cases. A considerable phenotypic variability was observed, with no clear genotype-phenotype correlations. Overall, our study represents the largest NNO and MCOP cohort reported to date and provides a genetic diagnosis in 19/21 families (90.5%), including the first MFRP genomic rearrangement, offering opportunities for gene-based therapies in MFRP-associated disease. Finally, our study underscores the importance of sequence and copy number analysis of the MFRP and PRSS56 genes in MCOP and NNO.
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http://dx.doi.org/10.1038/s41598-019-57338-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987234PMC
January 2020

Functional characterization of novel MFSD8 pathogenic variants anticipates neurological involvement in juvenile isolated maculopathy.

Clin Genet 2020 03 12;97(3):426-436. Epub 2019 Dec 12.

Center for Medical Genetics, Ghent University, Ghent, Belgium.

Biallelic MFSD8 variants are an established cause of severe late-infantile subtype of neuronal ceroid lipofuscinosis (v-LINCL), a severe lysosomal storage disorder, but have also been associated with nonsyndromic adult-onset maculopathy. Here, we functionally characterized two novel MFSD8 variants found in a child with juvenile isolated maculopathy, in order to establish a refined prognosis. ABCA4 locus resequencing was followed by the analysis of other inherited retinal disease genes by whole exome sequencing (WES). Minigene assays and cDNA sequencing were used to assess the effect of a novel MFSD8 splice variant. MFSD8 expression was quantified with qPCR and overexpression studies were analyzed by immunoblotting. Transmission electron microscopy (TEM) was performed on a skin biopsy and ophthalmological and neurological re-examinations were conducted. WES revealed two novel MFSD8 variants: c.[590del];[439+3A>C] p.[Gly197Valfs*2];[Ile67Glufs*3]. Characterization of the c.439+3A>C variant via splice assays showed exon-skipping (p.Ile67Glufs*3), while overexpression studies of the corresponding protein indicated expression of a truncated polypeptide. In addition, a significantly reduced MFSD8 RNA expression was noted in patient's lymphocytes. TEM of a skin biopsy revealed typical v-LINCL lipopigment inclusions while neurological imaging of the proband displayed subtle cerebellar atrophy. Functional characterization demonstrated the pathogenicity of two novel MFSD8 variants, found in a child with an initial diagnosis of juvenile isolated maculopathy but likely evolving to v-LINCL with a protracted disease course. Our study allowed a refined neurological prognosis in the proband and expands the natural history of MFSD8-associated disease.
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http://dx.doi.org/10.1111/cge.13673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064892PMC
March 2020

Mitochondrial single-stranded DNA binding protein novel de novo SSBP1 mutation in a child with single large-scale mtDNA deletion (SLSMD) clinically manifesting as Pearson, Kearns-Sayre, and Leigh syndromes.

PLoS One 2019 3;14(9):e0221829. Epub 2019 Sep 3.

Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.

Mitochondrial DNA (mtDNA) genome integrity is essential for proper mitochondrial respiratory chain function to generate cellular energy. Nuclear genes encode several proteins that function at the mtDNA replication fork, including mitochondrial single-stranded DNA-binding protein (SSBP1), which is a tetrameric protein that binds and protects single-stranded mtDNA (ssDNA). Recently, two studies have reported pathogenic variants in SSBP1 associated with hearing loss, optic atrophy, and retinal degeneration. Here, we report a 14-year-old Chinese boy with severe and progressive mitochondrial disease manifestations across the full Pearson, Kearns-Sayre, and Leigh syndromes spectrum, including infantile anemia and bone marrow failure, growth failure, ptosis, ophthalmoplegia, ataxia, severe retinal dystrophy of the rod-cone type, sensorineural hearing loss, chronic kidney disease, multiple endocrine deficiencies, and metabolic strokes. mtDNA genome sequencing identified a single large-scale 5 kilobase mtDNA deletion (m.8629_14068del5440), present at 68% and 16% heteroplasmy in the proband's fibroblast cell line and blood, respectively, suggestive of a mtDNA maintenance defect. On trio whole exome blood sequencing, the proband was found to harbor a novel de novo heterozygous mutation c.79G>A (p.E27K) in SSBP1. Size exclusion chromatography of p.E27K SSBP1 revealed it remains a stable tetramer. However, differential scanning fluorimetry demonstrated p.E27K SSBP1 relative to wild type had modestly decreased thermostability. Functional assays also revealed p.E27K SSBP1 had altered DNA binding. Molecular modeling of SSBP1 tetramers with varying combinations of mutant subunits predicted general changes in surface accessible charges, strength of inter-subunit interactions, and protein dynamics. Overall, the observed changes in protein dynamics and DNA binding behavior suggest that p.E27K SSBP1 can interfere with DNA replication and precipitate the introduction of large-scale mtDNA deletions. Thus, a single large-scale mtDNA deletion (SLSMD) with manifestations across the clinical spectrum of Pearson, Kearns-Sayre, and Leigh syndromes may result from a nuclear gene disorder disrupting mitochondrial DNA replication.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221829PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719858PMC
March 2020

Long-Term Follow-Up of Retinal Degenerations Associated With Mutations and Their Comparability to Phenotypes Associated With Mutations.

Transl Vis Sci Technol 2019 Jul 19;8(4):24. Epub 2019 Aug 19.

Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.

Purpose: To investigate the natural history in patients with -associated retinal degenerations (RDs), in the advent of clinical trials testing treatment options.

Methods: A retrospective cohort of 13 patients with -RDs.

Results: Twelve patients from a genetic isolate carried a homozygous c.12del mutation. One unrelated patient carried a homozygous c.326G>T mutation. The mean follow-up time was 25.3 years (SD 15.2; range 4.8-53.5). The first symptom was nyctalopia ( = 11), central vision loss ( = 1), or light-gazing ( = 1), and was noticed in the first decade of life. Seven patients (54%) reached low vision (visual acuity < 20/67), four of whom reaching blindness (visual acuity < 20/400), respectively, at mean ages of 49.9 (SE 5.4) and 59.9 (SE 3.1) years. The fundus appearance was variable. Retinal white dots were seen in six patients (46%). Full-field electroretinograms ( = 11) were nondetectable ( = 2; ages 31-60), reduced in a nonspecified pattern ( = 2; ages 11-54), or showed rod-cone ( = 6; ages 38-48) or cone-rod ( = 1; age 29) dysfunction. Optical coherence tomography ( = 4) showed retinal thinning but relative preservation of the (para-)foveal outer retinal layers in the second ( = 1) and sixth decade of life ( = 2), and profound chorioretinal degeneration from the eighth decade of life ( = 1).

Conclusions: -associated phenotypes in this cohort were variable and unusual, but generally milder than those seen in -associated disease, and may be particularly amenable to treatment. The window of therapeutic opportunity can be extended in patients with a mild phenotype.

Translational Relevance: Knowledge of the natural history of -RDs is essential in determining the window of opportunity in ongoing and future clinical trials for novel therapeutic options.
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http://dx.doi.org/10.1167/tvst.8.4.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703192PMC
July 2019

Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation-Associated Inherited Retinal Dystrophy: Results of Phase 1 and 3 Trials.

Ophthalmology 2019 09 22;126(9):1273-1285. Epub 2019 Jun 22.

Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Cellular and Molecular Therapeutics, Inc., Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Purpose: To report the durability of voretigene neparvovec-rzyl (VN) adeno-associated viral vector-based gene therapy for RPE65 mutation-associated inherited retinal dystrophy (IRD), including results of a phase 1 follow-on study at year 4 and phase 3 study at year 2.

Design: Open-label phase 1 follow-on clinical trial and open-label, randomized, controlled phase 3 clinical trial.

Participants: Forty subjects who received 1.5×10 vector genomes (vg) of VN per eye in at least 1 eye during the trials, including 11 phase 1 follow-on subjects and 29 phase 3 subjects (20 original intervention [OI] and 9 control/intervention [CI]).

Methods: Subretinal injection of VN in the second eye of phase 1 follow-on subjects and in both eyes of phase 3 subjects.

Main Outcome Measures: End points common to the phase 1 and phase 3 studies included change in performance on the Multi-Luminance Mobility Test (MLMT) within the illuminance range evaluated, full-field light sensitivity threshold (FST) testing, and best-corrected visual acuity (BCVA). Safety end points included adverse event reporting, ophthalmic examination, physical examination, and laboratory testing.

Results: Mean (standard deviation) MLMT lux score change was 2.4 (1.3) at 4 years compared with 2.6 (1.6) at 1 year after administration in phase 1 follow-on subjects (n = 8), 1.9 (1.1) at 2 years, and 1.9 (1.0) at 1 year post-administration in OI subjects (n = 20), and 2.1 (1.6) at 1 year post-administration in CI subjects (n = 9). All 3 groups maintained an average improvement in FST, reflecting more than a 2 log(cd.s/m) improvement in light sensitivity at 1 year and subsequent available follow-up visits. The safety profile was consistent with vitrectomy and the subretinal injection procedure, and no deleterious immune responses occurred.

Conclusions: After VN gene augmentation therapy, there was a favorable benefit-to-risk profile with similar improvement demonstrated in navigational ability and light sensitivity among 3 groups of subjects with RPE65 mutation-associated IRD, a degenerative disease that progresses to complete blindness. The safety profile is consistent with the administration procedure. These data suggest that this effect, which is nearly maximal by 30 days after VN administration, is durable for 4 years, with observation ongoing.
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http://dx.doi.org/10.1016/j.ophtha.2019.06.017DOI Listing
September 2019

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders.

Hum Mutat 2019 06 28;40(6):765-787. Epub 2019 Mar 28.

INSERM, CNRS, Institut de la Vision, Sorbonne Université, Paris, France.

Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.
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http://dx.doi.org/10.1002/humu.23735DOI Listing
June 2019

ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants.

Genet Med 2019 08 23;21(8):1761-1771. Epub 2019 Jan 23.

Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.

Purpose: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability.

Methods: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4.

Results: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells.

Conclusion: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders.
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http://dx.doi.org/10.1038/s41436-018-0420-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752479PMC
August 2019

The N-terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond.

Hum Mutat 2019 05 6;40(5):539-551. Epub 2019 Feb 6.

Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.

Sorsby fundus dystrophy (SFD) is a macular degeneration caused by mutations in TIMP3, the majority of which introduce a novel cysteine. However, the exact molecular mechanisms underlying SFD remain unknown. We aimed to provide novel insights into the functional consequences of a distinct N-terminal mutation. Haplotype reconstruction in three SFD families revealed that the identified c.113C>G, p.(Ser38Cys) mutation is a founder in Belgian and northern French families with a late-onset SFD phenotype. Functional consequences of the p.(Ser38Cys) mutation were investigated by high-resolution Western blot analysis of wild type and mutant TIMP3 using patient fibroblasts and in vitro generated proteins, and by molecular modeling of TIMP3 and its interaction partners. We could not confirm a previous hypothesis on dimerization of mutant TIMP3 proteins. However, we identified aberrant intramolecular disulfide bonding. Our data provide evidence for disruption of the established Cys36-Cys143 disulfide bond and formation of a novel Cys36-Cys38 bond, possibly associated with increased glycosylation of the protein. In conclusion, we propose a novel pathogenetic mechanism underlying the p.(Ser38Cys) TIMP3 founder mutation involving intramolecular disulfide bonding. These results provide new insights into the pathogenesis of SFD and other retinopathies linked to mutations in TIMP3, such as age-related macular degeneration.
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http://dx.doi.org/10.1002/humu.23713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594137PMC
May 2019

Ocular involvement in systemic sclerosis: A systematic literature review, it's not all scleroderma that meets the eye.

Semin Arthritis Rheum 2019 08 28;49(1):119-125. Epub 2018 Dec 28.

Department of Internal Medicine, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium; Department of Rheumatology, Ghent University Hospital, Corneel Heymanslaan 10, Ghent, Belgium; Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center (IRC), Corneel Heymanslaan 10, 9000 Ghent, Belgium. Electronic address:

Objectives: Systemic sclerosis (SSc) is a rare and complex autoimmune disorder characterized by microvascular damage and progressive fibrosis which affects the skin and multiple other organs. Much of the published data concerning SSc and the eye consists of single case reports or small case studies. This systematic review aims to provide an overview of the current level of evidence for SSc-related ocular changes.

Materials And Methods: A systematic literature review was conducted using 3 electronic databases, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. A combination of following keywords was used: "Systemic Sclerosis" and ophthalmology-related search terms, including the keywords "Eye", "Ocular" and "Ophthalmic". All articles were screened by 2 independent reviewers at title, abstract and full text level. We solely included case-control studies that investigated specific ocular findings in SSc patients compared to healthy controls.

Results: Nine of 270 articles were retained. Dry eye symptoms are associated with SSc, whereas objective signs (Schirmer I testing) show conflicting results. There is insufficient evidence of SSc-related changes to the central corneal thickness. In terms of posterior segment involvement, choroidal vasculature appears to be affected to greater extent than the retinal microcirculation. However, the limited number of patients included in the studies renders it hazardous to draw overall conclusions.

Conclusions: There is a paucity of well-designed case-control studies investigating possible ocular involvement in SSc. Our systematic review demonstrates limited proven associations between SSc and ocular abnormalities, mainly in terms of dry eye symptoms and choroidal thickness. Future standardized prospective studies are needed to clarify the impact of the disease on the eye.
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http://dx.doi.org/10.1016/j.semarthrit.2018.12.007DOI Listing
August 2019

Correction: Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease.

Genet Med 2019 04;21(4):1028

Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

The original version of this Article contained an incorrect version of Fig. 3, which included two variants initially shown in black text in Fig. 3a that the authors removed from the final manuscript. The correct version of Fig. 3 without the two variants now appears in the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0392-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752296PMC
April 2019

Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect.

Nat Med 2019 02 17;25(2):225-228. Epub 2018 Dec 17.

Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.

Photoreceptor ciliopathies constitute the most common molecular mechanism of the childhood blindness Leber congenital amaurosis. Ten patients with Leber congenital amaurosis carrying the c.2991+1655A>G allele in the ciliopathy gene centrosomal protein 290 (CEP290) were treated (ClinicalTrials.gov no. NCT03140969 ) with intravitreal injections of an antisense oligonucleotide to restore correct splicing. There were no serious adverse events, and vision improved at 3 months. The visual acuity of one exceptional responder improved from light perception to 20/400.
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http://dx.doi.org/10.1038/s41591-018-0295-0DOI Listing
February 2019

Abetalipoproteinemia From Previously Unreported Gene Mutations.

Ann Intern Med 2019 02 6;170(3):211-213. Epub 2018 Nov 6.

Ghent University Hospital and Ghent University, Ghent, Belgium (X.A., B.P.L., S.S.).

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http://dx.doi.org/10.7326/L18-0358DOI Listing
February 2019

Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease.

Genet Med 2019 06 31;21(6):1319-1329. Epub 2018 Oct 31.

Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

Purpose: RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease.

Methods: Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members.

Results: Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry.

Conclusion: This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases.
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http://dx.doi.org/10.1038/s41436-018-0345-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752271PMC
June 2019

Correction: Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations.

Genet Med 2019 Aug;21(8):1998

Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

The original version of this Article contained an error in the spelling of the author Anja K. Mayer, which was incorrectly given as Anja Kathrin Mayer. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0305-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609298PMC
August 2019