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2. Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation.

Author

Carelli, Valerio, Newman, Nancy, Yu-Wai-Man, Patrick, Biousse, Valerie, Moster, Mark, Subramanian, Prem, Vignal-Clermont, Catherine, Wang, An-Guor, Donahue, Sean, Leroy, Bart, Sergott, Robert, Klopstock, Thomas, Sadun, Alfredo, Rebolleda Fernández, Gema, Chwalisz, Bart, Banik, Rudrani, Girmens, Jean, La Morgia, Chiara, DeBusk, Adam, Jurkute, Neringa, Priglinger, Claudia, Karanjia, Rustum, Josse, Constant, Salzmann, Julie, Montestruc, François, Roux, Michel, Taiel, Magali, and Sahel, José-Alain

Subjects
Gene therapy, LHON, Leber hereditary optic neuropathy, MT-ND4, Natural history, Visual acuity
Abstract

INTRODUCTION: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. METHODS: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. RESULTS: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P

Published
2023

3. Multidisciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies

Author

Varela, Malena Daich, Bellingham, James, Motta, Fabiana, Jurkute, Neringa, Ellingford, Jamie M, Quinodoz, Mathieu, Oprych, Kathryn, Niblock, Michael, Janeschitz-Kriegl, Lucas, Kaminska, Karolina, Cancellieri, Francesca, Scholl, Hendrik PN, Lenassi, Eva, Schiff, Elena, Knight, Hannah, Black, Graeme, Rivolta, Carlo, Cheetham, Michael E, Michaelides, Michel, Mahroo, Omar A, Moore, Anthony T, Webster, Andrew R, and Arno, Gavin

Subjects
Biological Sciences, Genetics, Human Genome, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Humans, Mutation, Pedigree, Retinal Dystrophies, Whole Genome Sequencing, Patient Care Team, DNA Mutational Analysis, Eye Proteins, Membrane Proteins, Nerve Tissue Proteins, Medical and Health Sciences, Genetics & Heredity
Abstract

The purpose of this paper is to identify likely pathogenic non-coding variants in inherited retinal dystrophy (IRD) genes, using genome sequencing (GS). Patients with IRD were recruited to the study and underwent comprehensive ophthalmological evaluation and GS. The results of GS were investigated through virtual gene panel analysis, and plausible pathogenic variants and clinical phenotype evaluated by the multidisciplinary team (MDT) discussion. For unsolved patients in whom a specific gene was suspected to harbor a missed pathogenic variant, targeted re-analysis of non-coding regions was performed on GS data. Candidate variants were functionally tested by messenger RNA analysis, minigene or luciferase reporter assays. Previously unreported, likely pathogenic, non-coding variants in 7 genes (PRPF31, NDP, IFT140, CRB1, USH2A, BBS10 and GUCY2D), were identified in 11 patients. These were shown to lead to mis-splicing (PRPF31, IFT140, CRB1 and USH2A) or altered transcription levels (BBS10 and GUCY2D). MDT-led, phenotype-driven, non-coding variant re-analysis of GS is effective in identifying the missing causative alleles.

Published
2023

4. Spectrum of Genetic Variants in the Most Common Genes Causing Inherited Retinal Disease in a Large Molecularly Characterized United Kingdom Cohort

Author

Lin, Siying, Vermeirsch, Sandra, Pontikos, Nikolas, Martin-Gutierrez, Maria Pilar, Daich Varela, Malena, Malka, Samantha, Schiff, Elena, Knight, Hannah, Wright, Genevieve, Jurkute, Neringa, Simcoe, Mark J., Yu-Wai-Man, Patrick, Moosajee, Mariya, Michaelides, Michel, Mahroo, Omar A., Webster, Andrew R., and Arno, Gavin

Published
2024
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5. Natural history of patients with Leber hereditary optic neuropathy-results from the REALITY study.

Author

Yu-Wai-Man, Patrick, Newman, Nancy, Carelli, Valerio, La Morgia, Chiara, Biousse, Valérie, Bandello, Francesco, Clermont, Catherine, Campillo, Lorena, Leruez, Stephanie, Moster, Mark, Cestari, Dean, Foroozan, Rod, Sadun, Alfredo, Karanjia, Rustum, Jurkute, Neringa, Blouin, Laure, Taiel, Magali, and Sahel, José-Alain

Subjects
Adolescent, Adult, DNA, Mitochondrial, Europe, Humans, Mutation, Optic Atrophy, Hereditary, Leber, Retrospective Studies
Abstract

BACKGROUND/OBJECTIVES: REALITY is an international observational retrospective registry of LHON patients evaluating the visual course and outcome in Leber hereditary optic neuropathy (LHON). SUBJECTS/METHODS: Demographics and visual function data were collected from medical charts of LHON patients with visual loss. The study was conducted in 11 study centres in the United States of America and Europe. The collection period extended from the presymptomatic stage to at least more than one year after onset of vision loss (chronic stage). A Locally Weighted Scatterplot Smoothing (LOWESS) local regression model was used to analyse the evolution of best-corrected visual acuity (BCVA) over time. RESULTS: 44 LHON patients were included; 27 (61%) carried the m.11778G>A ND4 mutation, 8 (18%) carried the m.3460G>A ND1 mutation, and 9 (20%) carried the m.14484T>C ND6 mutation. Fourteen (32%) patients were under 18 years old at onset of vision loss and 5 (11%) were below the age of 12. The average duration of follow-up was 32.5 months after onset of symptoms. At the last observed measure, mean BCVA was 1.46 LogMAR in ND4 patients, 1.52 LogMAR in ND1 patients, and 0.97 LogMAR in ND6 patients. The worst visual outcomes were reported in ND4 patients aged at least 15 years old at onset, with a mean BCVA of 1.55 LogMAR and no tendency for spontaneous recovery. The LOESS modelling curve depicted a severe and permanent deterioration of BCVA. CONCLUSIONS: Amongst LHON patients with the three primary mtDNA mutations, adult patients with the m.11778G>A ND4 mutation had the worst visual outcomes, consistent with prior reports.

Published
2022

7. Application of a Deep Learning System to Detect Papilledema on Nonmydriatic Ocular Fundus Photographs in an Emergency Department

Author

Fraser, Clare L., Micieli, Jonathan A., Costello, Fiona, Bénard-Séguin, Étienne, Yang, Hui, Chan, Carmen Kar Mun, Cheung, Carol Y, Chan, Noel CY, Hamann, Steffen, Gohier, Philippe, Vautier, Anaïs, Rougier, Marie-Bénédicte, Chiquet, Christophe, Vignal-Clermont, Catherine, Hage, Rabih, Khanna, Raoul Kanav, Tran, Thi Ha Chau, Lagrèze, Wolf Alexander, Jonas, Jost B, Ambika, Selvakumar, Fard, Masoud Aghsaei, La Morgia, Chiara, Carbonelli, Michele, Barboni, Piero, Carelli, Valerio, Romagnoli, Martina, Amore, Giulia, Nakamura, Makoto, Fumio, Takano, Petzold, Axel, Wenniger lj, Maillette de Buy, Kho, Richard, Fonseca, Pedro L., Bikbov, Mukharram M., Milea, Dan, Najjar, Raymond P, Ting, Daniel, Tang, Zhiqun, Loo, Jing Liang, Tow, Sharon, Singhal, Shweta, Vasseneix, Caroline, Wong, Tien Yin, Lamoureux, Ecosse, Yu Chen, Ching, Aung, Tin, Schmetterer, Leopold, Sanda, Nicolae, Thuman, Gabriele, Hwang, Jeong-Min, Vanikieti, Kavin, Suwan, Yanin, Padungkiatsagul, Tanyatuth, Yu-Wai-Man, Patrick, Jurkute, Neringa, Hong, Eun Hee, Biousse, Valerie, Newman, Nancy J., Peragallo, Jason H., Datillo, Michael, Kedar, Sachin, Lin, Mung Yan, Patil, Ajay, Aung, Andre, Boyko, Matthew, Alsakran, Wael Abdulraman, Zayani, Amani, Bouthour, Walid, Banc, Ana, Mosley, Rasha, Labella, Fernando, Miller, Neil R., Chen, John J., Mejico, Luis J., Kilangalanga, Janvier Ngoy, Biousse, Valérie, Najjar, Raymond P., Wright, David W., Keadey, Matthew T., Wong, Tien Y., and Bruce, Beau B.

Published
2024
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8. Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial

Author

Yu-Wai-Man, Patrick, Carelli, Valerio, Newman, Nancy J., Silva, Magda Joana, Linden, Aki, Van Stavern, Gregory, Szaflik, Jacek P., Banik, Rudrani, Lubiński, Wojciech, Pemp, Berthold, Liao, Yaping Joyce, Subramanian, Prem S., Misiuk-Hojło, Marta, Newman, Steven, Castillo, Lorena, Kocięcki, Jarosław, Levin, Marc H., Muñoz-Negrete, Francisco Jose, Yagan, Ali, Cherninkova, Sylvia, Katz, David, Meunier, Audrey, Votruba, Marcela, Korwin, Magdalena, Dziedziak, Jacek, Jurkutė, Neringa, Harvey, Joshua P., La Morgia, Chiara, Priglinger, Claudia, Llòria, Xavier, Tomasso, Livia, and Klopstock, Thomas

Published
2024
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9. SSBP1-Disease Update: Expanding the Genetic and Clinical Spectrum, Reporting Variable Penetrance and Confirming Recessive Inheritance

Author

Jurkute, Neringa, D'Esposito, Fabiana, Robson, Anthony G, Pitceathly, Robert DS, Cordeiro, Francesca, Raymond, F Lucy, Moore, Anthony T, Michaelides, Michel, Yu-Wai-Man, Patrick, Webster, Andrew R, and Arno, Gavin

Subjects
Human Genome, Genetics, Neurosciences, Eye Disease and Disorders of Vision, Rare Diseases, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Eye, Good Health and Well Being, Adolescent, Amino Acid Sequence, Child, Preschool, DNA, Mitochondrial, DNA-Binding Proteins, Electroretinography, Female, Genes, Recessive, Genotyping Techniques, Humans, Male, Middle Aged, Mitochondrial Diseases, Mitochondrial Proteins, Molecular Conformation, Molecular Sequence Data, Mutation, Missense, Optic Atrophy, Pedigree, Penetrance, Protein Stability, Protein Structure, Quaternary, Retinal Dystrophies, Whole Genome Sequencing, SSBP1, mtSSB, mtDNA replication, inherited optic neuropathy, retinal dystrophy, Genomics England Research Consortium, Biological Sciences, Medical and Health Sciences, Ophthalmology & Optometry
Abstract

PurposeTo report novel genotypes and expand the phenotype spectrum of SSBP1-disease and explore potential disease mechanism.MethodsFive families with previously unsolved optic atrophy and retinal dystrophy underwent whole genome sequencing as part of the National Institute for Health Research BioResource Rare-Diseases and the UK's 100,000 Genomes Project. In silico analysis and protein modelling was performed on the identified variants. Deep phenotyping including retinal imaging and International Society for Clinical Electrophysiology of Vision standard visual electrophysiology was performed.ResultsSeven individuals from five unrelated families with bilateral optic atrophy and/or retinal dystrophy with extraocular signs and symptoms in some are described. In total, 6 SSBP1 variants were identified including the previously unreported variants: c.151A>G, p.(Lys51Glu), c.335G>A p.(Gly112Glu), and c.380G>A, p.(Arg127Gln). One individual was found to carry biallelic variants (c.380G>A p.(Arg127Gln); c.394A>G p.(Ile132Val)) associated with likely autosomal recessive SSBP1-disease. In silico analysis predicted all variants to be pathogenic and Three-dimensional protein modelling suggested possible disease mechanisms via decreased single-stranded DNA binding affinity or impaired higher structure formation.ConclusionsSSBP1 is essential for mitochondrial DNA replication and maintenance, with defects leading to a spectrum of disease that includes optic atrophy and/or retinal dystrophy, occurring with or without extraocular features. This study provides evidence of intrafamilial variability and confirms the existence of an autosomal recessive inheritance in SSBP1-disease consequent upon a previously unreported genotype.

Published
2021

10. The BONSAI (Brain and Optic Nerve Study with Artificial Intelligence) deep learning system can accurately identify pediatric papilledema on standard ocular fundus photographs

Author

Fraser, Clare L., Micieli, Jonathan A., Costello, Fiona, Étienne Bénard-Séguin, Yang, Hui, Mun Chan, Carmen Kar, Cheung, Carol Y., Chan, Noel CY., Hamann, Steffen, Gohier, Philippe, Vautier, Anaïs, Rougier, Marie-Bénédicte, Chiquet, Christophe, Vignal-Clermont, Catherine, Hage, Rabih, Khanna, Raoul Kanav, Chau Tran, Thi Ha, Lagrèze, Wolf Alexander, Jonas, Jost B., Ambika, Selvakumar, Fard, Masoud Aghsaei, La Morgia, Chiara, Carbonelli, Michele, Barboni, Piero, Carelli, Valerio, Romagnoli, Martina, Amore, Giulia, Nakamura, Makoto, Fumio, Takano, Petzold, Axel, de Buy Wenniger L.J., Maillette, Kho, Richard, Fonseca, Pedro L., Bikbov, Mukharram M., Milea, Dan, Najjar, Raymond P., Ting, Daniel, Tang, Zhiqun, Loo, Jing Liang, Tow, Sharon, Singhal, Shweta, Vasseneix, Caroline, Wong, Tien Yin, Lamoureux, Ecosse, Chen, Ching Yu, Aung, Tin, Schmetterer, Leopold, Sanda, Nicolae, Thuman, Gabriele, Hwang, Jeong-Min, Vanikieti, Kavin, Suwan, Yanin, Padungkiatsagul, Tanyatuth, Yu-Wai-Man, Patrick, Jurkute, Neringa, Hong, Eun Hee, Biousse, Valerie, Newman, Nancy J., Peragallo, Jason H., Datillo, Michael, Kedar, Sachin, Lin, Mung Yan, Patil, Ajay, Aung, Andre, Boyko, Matthew, Alsakran, Wael Abdulraman, Zayani, Amani, Bouthour, Walid, Banc, Ana, Mosley, Rasha, Labella, Fernando, Miller, Neil R., Chen, John J., Mejico, Luis J., Kilangalanga, Janvier Ngoy, Cioplean, Daniela, Dragomir, Mihaela, Chia, Audrey, and Biousse, Valérie

Published
2024
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11. Expanding the FDXR-Associated Disease Phenotype: Retinal Dystrophy Is a Recurrent Ocular Feature

Author

Jurkute, Neringa, Shanmugarajah, Priya D, Hadjivassiliou, Marios, Higgs, Jenny, Vojcic, Miodrag, Horrocks, Iain, Nadjar, Yann, Touitou, Valerie, Lenaers, Guy, Poh, Roy, Acheson, James, Robson, Anthony G, Raymond, F Lucy, Reilly, Mary M, Yu-Wai-Man, Patrick, Moore, Anthony T, Webster, Andrew R, Arno, Gavin, and Consortium, for the Genomics England Research

Subjects
Rare Diseases, Clinical Research, Genetics, Biotechnology, Neurosciences, Eye Disease and Disorders of Vision, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Eye, Adolescent, Adult, Child, Child, Preschool, Electroretinography, Female, Ferredoxin-NADP Reductase, Humans, Male, Mutation, Missense, Pedigree, Phenotype, Retina, Retinal Dystrophies, Retrospective Studies, Visual Acuity, Exome Sequencing, Young Adult, FDXR, ferredoxin reductase, syndromic optic neuropathy, retinal dystrophy, neurodegenerative disorder, iron accumulation, Genomics England Research Consortium, Biological Sciences, Medical and Health Sciences, Ophthalmology & Optometry
Abstract

PurposeThe purpose of this study was to report retinal dystrophy as a novel clinical feature and expand the ocular phenotype in patients harboring biallelic candidate FDXR variants.MethodsPatients carrying biallelic candidate FDXR variants were identified by whole genome sequencing (WGS) as part of the National Institute for Health Research BioResource rare-disease and the UK's 100,000 Genomes Project (100KGP) with an additional case identified by exome sequencing. Retrospective clinical data were collected from the medical records. Haplotype reconstruction was performed in families harboring the same missense variant.ResultsTen individuals from 8 unrelated families with biallelic candidate variants in FDXR were identified. In addition to bilateral optic atrophy and variable extra-ocular findings, 7 of 10 individuals manifested retinal dystrophy comprising dysfunction and degeneration of both rod and cone photoreceptors. Five of 10 subjects had sensorineural hearing loss. The previously unreported missense variant (c.1115C > A, p.(Pro372His)) was found in 5 of 8 (62.5%) study families. Haplotype reconstruction using WGS data demonstrated a likely ancestral haplotype.ConclusionsFDXR-associated disease is a phenotypically heterogeneous disorder with retinal dystrophy being a major clinical feature observed in this cohort. In addition, we hypothesize that a number of factors are likely to drive the pathogenesis of optic atrophy, retinal degeneration, and perhaps the associated systemic manifestations.

Published
2021

12. Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison.

Author

Newman, Nancy, Yu-Wai-Man, Patrick, Carelli, Valerio, Biousse, Valerie, Moster, Mark, Vignal-Clermont, Catherine, Sergott, Robert, Klopstock, Thomas, Sadun, Alfredo, Girmens, Jean-François, La Morgia, Chiara, DeBusk, Adam, Jurkute, Neringa, Priglinger, Claudia, Karanjia, Rustum, Josse, Constant, Salzmann, Julie, Montestruc, François, Roux, Michel, Taiel, Magali, and Sahel, José-Alain

Subjects
Leber hereditary optic neuropathy, ND4, gene therapy, natural history, visual acuity
Abstract

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies. Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control. Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss. Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences. Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4. Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of -0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (-0.32 LogMAR, p < 0.0001). Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies. Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.

Published
2021

13. Genetic Basis of Inherited Retinal Disease in a Molecularly Characterized Cohort of More Than 3000 Families from the United Kingdom

Author

Pontikos, Nikolas, Arno, Gavin, Jurkute, Neringa, Schiff, Elena, Ba-Abbad, Rola, Malka, Samantha, Gimenez, Ainoa, Georgiou, Michalis, Wright, Genevieve, Armengol, Monica, Knight, Hannah, Katz, Menachem, Moosajee, Mariya, Yu-Wai-Man, Patrick, Moore, Anthony T, Michaelides, Michel, Webster, Andrew R, and Mahroo, Omar A

Subjects
Genetics, Eye Disease and Disorders of Vision, Clinical Research, DNA, DNA Mutational Analysis, Eye Proteins, Female, Genetic Testing, Humans, Male, Mutation, Pedigree, Retina, Retinal Diseases, Retrospective Studies, United Kingdom, Clinical Sciences, Opthalmology and Optometry, Public Health and Health Services, Ophthalmology & Optometry
Abstract

PurposeIn a large cohort of molecularly characterized inherited retinal disease (IRD) families, we investigated proportions with disease attributable to causative variants in each gene.DesignRetrospective study of electronic patient records.ParticipantsPatients and relatives managed in the Genetics Service of Moorfields Eye Hospital in whom a molecular diagnosis had been identified.MethodsGenetic screening used a combination of single-gene testing, gene panel testing, whole exome sequencing, and more recently, whole genome sequencing. For this study, genes listed in the Retinal Information Network online resource (https://sph.uth.edu/retnet/) were included. Transcript length was extracted for each gene (Ensembl, release 94).Main outcome measuresWe calculated proportions of families with IRD attributable to variants in each gene in the entire cohort, a cohort younger than 18 years, and a current cohort (at least 1 patient encounter between January 1, 2017, and August 2, 2019). Additionally, we explored correlation between numbers of families and gene transcript length.ResultsWe identified 3195 families with a molecular diagnosis (variants in 135 genes), including 4236 affected individuals. The pediatric cohort comprised 452 individuals from 411 families (66 genes). The current cohort comprised 2614 families (131 genes; 3130 affected individuals). The 20 most frequently implicated genes overall (with prevalence rates per families) were as follows: ABCA4 (20.8%), USH2A (9.1%), RPGR (5.1%), PRPH2 (4.6%), BEST1 (3.9%), RS1 (3.5%), RP1 (3.3%), RHO (3.3%), CHM (2.7%), CRB1 (2.1%), PRPF31 (1.8%), MY07A (1.7%), OPA1 (1.6%), CNGB3 (1.4%), RPE65 (1.2%), EYS (1.2%), GUCY2D (1.2%), PROM1 (1.2%), CNGA3 (1.1%), and RDH12 (1.1%). These accounted for 71.8% of all molecularly diagnosed families. Spearman coefficients for correlation between numbers of families and transcript length were 0.20 (P = 0.025) overall and 0.27 (P = 0.017), -0.17 (P = 0.46), and 0.71 (P = 0.047) for genes in which variants exclusively cause recessive, dominant, or X-linked disease, respectively.ConclusionsOur findings help to quantify the burden of IRD attributable to each gene. More than 70% of families showed pathogenic variants in 1 of 20 genes. Transcript length (relevant to gene delivery strategies) correlated significantly with numbers of affected families (but not for dominant disease).

Published
2020

15. SSBP1 mutations in dominant optic atrophy with variable retinal degeneration

Author

Jurkute, Neringa, Leu, Costin, Pogoda, Hans‐Martin, Arno, Gavin, Robson, Anthony G, Nürnberg, Gudrun, Altmüller, Janine, Thiele, Holger, Motameny, Susanne, Toliat, Mohammad Reza, Powell, Kate, Höhne, Wolfgang, Michaelides, Michel, Webster, Andrew R, Moore, Anthony T, Hammerschmidt, Matthias, Nürnberg, Peter, Yu‐Wai‐Man, Patrick, and Votruba, Marcela

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Pediatric, Neurosciences, Eye Disease and Disorders of Vision, Rare Diseases, Neurodegenerative, Genetics, 2.1 Biological and endogenous factors, Aetiology, Eye, Animals, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Female, Gene Knockdown Techniques, Genetic Linkage, Genetic Predisposition to Disease, Humans, Male, Mice, Mitochondrial Proteins, Mutation, Missense, Optic Atrophy, Autosomal Dominant, Pedigree, RNA, Messenger, Retinal Degeneration, Zebrafish, Clinical Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveAutosomal dominant optic atrophy (ADOA) starts in early childhood with loss of visual acuity and color vision deficits. OPA1 mutations are responsible for the majority of cases, but in a portion of patients with a clinical diagnosis of ADOA, the cause remains unknown. This study aimed to identify novel ADOA-associated genes and explore their causality.MethodsLinkage analysis and sequencing were performed in multigeneration families and unrelated patients to identify disease-causing variants. Functional consequences were investigated in silico and confirmed experimentally using the zebrafish model.ResultsWe defined a new ADOA locus on 7q33-q35 and identified 3 different missense variants in SSBP1 (NM_001256510.1; c.113G>A [p.(Arg38Gln)], c.320G>A [p.(Arg107Gln)] and c.422G>A [p.(Ser141Asn)]) in affected individuals from 2 families and 2 singletons with ADOA and variable retinal degeneration. The mutated arginine residues are part of a basic patch that is essential for single-strand DNA binding. The loss of a positive charge at these positions is very likely to lower the affinity of SSBP1 for single-strand DNA. Antisense-mediated knockdown of endogenous ssbp1 messenger RNA (mRNA) in zebrafish resulted in compromised differentiation of retinal ganglion cells. A similar effect was achieved when mutated mRNAs were administered. These findings point toward an essential role of ssbp1 in retinal development and the dominant-negative nature of the identified human variants, which is consistent with the segregation pattern observed in 2 multigeneration families studied.InterpretationSSBP1 is an essential protein for mitochondrial DNA replication and maintenance. Our data have established pathogenic variants in SSBP1 as a cause of ADOA and variable retinal degeneration. ANN NEUROL 2019;86:368-383.

Published
2019

16. Biallelic variants in coenzyme Q10 biosynthesis pathway genes cause a retinitis pigmentosa phenotype

Author

Jurkute, Neringa, Cancellieri, Francesca, Pohl, Lisa, Li, Catherina H. Z., Heaton, Robert A., Reurink, Janine, Bellingham, James, Quinodoz, Mathieu, Yioti, Georgia, Stefaniotou, Maria, Weener, Marianna, Zuleger, Theresia, Haack, Tobias B., Stingl, Katarina, Hoyng, Carel B., Mahroo, Omar A., Hargreaves, Iain, Raymond, F. Lucy, Michaelides, Michel, Rivolta, Carlo, Kohl, Susanne, Roosing, Susanne, Webster, Andrew R., and Arno, Gavin

Published
2022
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17. Deep Learning System Outperforms Clinicians in Identifying Optic Disc Abnormalities

Author

Vasseneix, Caroline, Nusinovici, Simon, Xu, Xinxing, Hwang, Jeong-Min, Hamann, Steffen, Chen, John J., Loo, Jing Liang, Milea, Leonard, Tan, Kenneth B.K., Ting, Daniel S.W., Liu, Yong, Newman, Nancy J., Biousse, Valerie, Wong, Tien Ying, Milea, Dan, Najjar, Raymond P., Gohier, Philippe, Miller, Neil, Vanikieti, Kavin, La Morgia, Chiara, Rougier, Marie-Bénédicte, Ambika, Selvakumar, Fonseca, Pedro, Lagrèze, Wolf Alexander, Sanda, Nicolae, Chiquet, Christophe, Yang, Hui, Chan, Carmen K. M., Cheung, Carol Y., Ha Chau, Tran Thi, Jurkute, Neringa, Yu-Wai-Man, Patrick, Kho, Richard, Jonas, Jost B, Vignal-Clermont, Catherine, Kim, Dong Hyun, Yang, Hee Kyung, Aung, Tin, Singhal, Shweta, Tow, Sharon, Nongpiur, Monisha Esther, Perera, Shamira, Narayanaswamy, Arun, Thirugnanam, Umapathi N., Fraser, Clare L., Mejico, Luis J., and Fard, Masoud Aghsaei

Published
2023
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19. Application of a Deep Learning System to Detect Papilledema on Nonmydriatic Ocular Fundus Photographs in an Emergency Department

Author

Biousse, Valérie, primary, Najjar, Raymond P., additional, Tang, Zhiqun, additional, Lin, Mung Yan, additional, Wright, David W., additional, Keadey, Matthew T., additional, Wong, Tien Y., additional, Bruce, Beau B., additional, Milea, Dan, additional, Newman, Nancy J., additional, Fraser, Clare L., additional, Micieli, Jonathan A., additional, Costello, Fiona, additional, Bénard-Séguin, Étienne, additional, Yang, Hui, additional, Chan, Carmen Kar Mun, additional, Cheung, Carol Y, additional, Chan, Noel CY, additional, Hamann, Steffen, additional, Gohier, Philippe, additional, Vautier, Anaïs, additional, Rougier, Marie-Bénédicte, additional, Chiquet, Christophe, additional, Vignal-Clermont, Catherine, additional, Hage, Rabih, additional, Khanna, Raoul Kanav, additional, Tran, Thi Ha Chau, additional, Lagrèze, Wolf Alexander, additional, Jonas, Jost B, additional, Ambika, Selvakumar, additional, Fard, Masoud Aghsaei, additional, La Morgia, Chiara, additional, Carbonelli, Michele, additional, Barboni, Piero, additional, Carelli, Valerio, additional, Romagnoli, Martina, additional, Amore, Giulia, additional, Nakamura, Makoto, additional, Fumio, Takano, additional, Petzold, Axel, additional, Wenniger lj, Maillette de Buy, additional, Kho, Richard, additional, Fonseca, Pedro L., additional, Bikbov, Mukharram M., additional, Najjar, Raymond P, additional, Ting, Daniel, additional, Loo, Jing Liang, additional, Tow, Sharon, additional, Singhal, Shweta, additional, Vasseneix, Caroline, additional, Wong, Tien Yin, additional, Lamoureux, Ecosse, additional, Yu Chen, Ching, additional, Aung, Tin, additional, Schmetterer, Leopold, additional, Sanda, Nicolae, additional, Thuman, Gabriele, additional, Hwang, Jeong-Min, additional, Vanikieti, Kavin, additional, Suwan, Yanin, additional, Padungkiatsagul, Tanyatuth, additional, Yu-Wai-Man, Patrick, additional, Jurkute, Neringa, additional, Hong, Eun Hee, additional, Biousse, Valerie, additional, Peragallo, Jason H., additional, Datillo, Michael, additional, Kedar, Sachin, additional, Patil, Ajay, additional, Aung, Andre, additional, Boyko, Matthew, additional, Alsakran, Wael Abdulraman, additional, Zayani, Amani, additional, Bouthour, Walid, additional, Banc, Ana, additional, Mosley, Rasha, additional, Labella, Fernando, additional, Miller, Neil R., additional, Chen, John J., additional, Mejico, Luis J., additional, and Kilangalanga, Janvier Ngoy, additional

Published
2024
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20. Study design and baseline characteristics for the reflect gene therapy trial ofm.11778g>A/ND4-LHON

Author

Nancy J Newman, Valérie Biousse, José-Alain Sahel, Patrick Yu-Wai-Man, Sean Donahue, Gema Rebolleda, Prem S Subramanian, Bart P Leroy, Alfredo A Sadun, Robert C Sergott, Catherine Vignal-Clermont, Bart K Chwalisz, Mark Moster, An-Guor Wang, Valerio Carelli, Rudrani Banik, Fabienne Bazin, Eric Cox, Michel Roux, Magali Taiel, Amore Giulia, Anand Shweta, Banik Rudrani, Barboni Piero, Biousse Valérie, Boston Hayley, Burale Asma, Carbonelli Michele, Carelli Valerio, Chen Celia, Cheng Hui-Chen, Cho Steve, K Chwalisz Bart, Contin Manuela, D’Agati Pietro, A DeBusk Adam, De Zaeytijd Julie, Dobbs Jannah, P Donahue Sean, DuBois Lindreth, Esposti Simona, Fernandes Filho Alcides, Fortin Elizabeth, Gangaputra Sapna, Gibbs Deborah, Girmens Jean François, Hage Rabih, A Haller Julia, Heilweil Gad, Hubbard III GeorgeBaker, Hwang Jeong-Min, Jaumendreu Urquijo Laia, Jurkute Neringa, Karanjia Rustum, Khemliche Wahiba, La Morgia Chiara, P Leroy Bart, Massini Maria, Mathias Marc, A Memon Muhammad, Mohamed Susan, L Moster Mark, J Muñoz NegreteFrancisco, J Newman Nancy, O’Keefe Ghazala, Patel Shriji, Pecen Paula, H Peragallo Jason, Plaine Lise, Preston Mary, Rebolleda Fernández Gema, Romagnoli Martina, A Sadun Alfredo, A Sahel José, SantaMaria Melissa, C Sergott Robert, S Subramanian Prem, Sun Chuanbin, Tai Katy, Tollis Heather, Tsui Irena, R Tucker William, Vignal-Clermont Catherine, Wang An-Guor, Wilkins Saige, and Yu-Wai-Man Patrick

Subjects
Ophthalmology, RE1-994
Abstract

Objective REFLECT is the first randomised, double-masked, placebo-controlled multicentre phase 3 clinical trial that evaluated the efficacy and safety of bilateral intravitreal (IVT) injection of lenadogene nolparvovec in subjects with Leber hereditary optic neuropathy carrying the m.11778G>A mutation.Methods and analysis A total of 98 subjects were enrolled with vision loss of ≤12 months. The subjects were randomised to one of two treatment arms with all subjects receiving an intravitreal (IVT) injection of lenadogene nolparvovec in their first affected eye and the second-affected eye randomised to receive IVT of either lenadogene nolparvovec or placebo.Results The majority of subjects were male with a mean duration of vision loss of 8.3 months. All but one subject experienced bilateral loss of vision at the time of injection. The mean best-corrected visual acuity of first-affected eyes was worse compared with second/not-yet-affected eyes. Analysis of retinal anatomical parameters showed increased thinning in the first-affected eyes when compared with the second/not-yet-affected eyes with both treatment arms showing significant changes compared with unaffected individuals.Conclusion The REFLECT trial is the third and the largest phase 3 clinical study evaluating lenadogene nolparvovec in m.11778G>A Leber hereditary optic neuropathy (LHON) subjects. The observed demographics in REFLECT are consistent with previous reports in LHON subjects in the acute and dynamic phases of LHON disease. Combined with the visual function and anatomical parameters obtained in the previous RESCUE and REVERSE trials, REFLECT has provided a uniformly collected data set that should help direct future LHON clinical trials.

Published
2022
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21. Investigating Splice Defects in USH2A Using Targeted Long-Read Sequencing.

Author

Chandrasekhar, Shwetha, Lin, Siying, Jurkute, Neringa, Oprych, Kathryn, Estramiana Elorrieta, Leire, Schiff, Elena, Malka, Samantha, Wright, Genevieve, Michaelides, Michel, Mahroo, Omar A., Webster, Andrew R., and Arno, Gavin

Subjects
WHOLE genome sequencing, VISION disorders, USHER'S syndrome, RETINITIS pigmentosa, EPITHELIAL cells
Abstract

Biallelic variants in USH2A are associated with retinitis pigmentosa (RP) and Type 2 Usher Syndrome (USH2), leading to impaired vision and, additionally, hearing loss in the latter. Although the introduction of next-generation sequencing into clinical diagnostics has led to a significant uplift in molecular diagnostic rates, many patients remain molecularly unsolved. It is thought that non-coding variants or variants of uncertain significance contribute significantly to this diagnostic gap. This study aims to demonstrate the clinical utility of the reverse transcription–polymerase chain reaction (RT-PCR)–Oxford Nanopore Technology (ONT) sequencing of USH2A mRNA transcripts from nasal epithelial cells to determine the splice-altering effect of candidate variants. Five affected individuals with USH2 or non-syndromic RP who had undergone whole genome sequencing were recruited for further investigation. All individuals had uncertain genotypes in USH2A, including deep intronic rare variants, c.8682-654C>G, c.9055+389G>A, and c.9959-2971C>T; a synonymous variant of uncertain significance, c.2139C>T; p.(Gly713=); and a predicted loss of function duplication spanning an intron/exon boundary, c.3812-3_3837dup p.(Met1280Ter). In silico assessment using SpliceAI provided splice-altering predictions for all candidate variants which were investigated using ONT sequencing. All predictions were found to be accurate; however, in the case of c.3812-3_3837dup, the outcome was a complex cryptic splicing pattern with predominant in-frame exon 18 skipping and a low level of exon 18 inclusion leading to the predicted stop gain. This study detected and functionally characterised simple and complex mis-splicing patterns in USH2A arising from previously unknown deep intronic variants and previously reported variants of uncertain significance, confirming the pathogenicity of the variants. [ABSTRACT FROM AUTHOR]

Published
2024
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24. PHOMS: An apt and accurate acronym

Author

Liu, Allison, Steensberg, Alvilda Hemmingsen, Gilbert, Aubrey L., Petzold, Axel, Katz, Bradley J., Fraser, Clare L., Milea, Dan, Costello, Fiona, Moss, Heather E., Shin, Hyunjin, Fraser, J. Alexander, Peragallo, Jason H., Gale, Jesse, Warner, Judith E.A., Digre, Kathleen B., Malmqvist, Lasse, Lykkebirk, Lea, Bursztyn, Lulu L.C.D., Rougier, Marie-Bénédicte, Fard, Masoud Aghsaei, El-Dairi, Mays A., Girard, Michael J.A., Lawlor, Mitchell, Rasool, Nailyn, Newman, Nancy J., Jurkute, Neringa, Sibony, Patrick A., Fonseca, Pedro, Quiros, Peter A., Maloca, Peter M., Subramanian, Prem S., Huna-Baron, Ruth, Beres, Shannon J., Bassi, Shikha Talwar, Rothenbuehler, Simon P., Wong, Sui H., Mollan, Susan P., Martín, Susana Noval, Biousse, Valerie, Shah, Veeral S., Liao, Yaping Joyce, Fraser, J.A., Costello, F., and Hamann, S.

Published
2024
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27. Optic Disc and Retinal Architecture Changes in Patients with Spinocerebellar Ataxia Type 2.

Author

Rezende Filho, Flávio Moura, Jurkute, Neringa, de Andrade, João Brainer Clares, Marianelli, Bruna Ferraço, de Lima, Fabrício Diniz, França, Marcondes Cavalcante, Sallum, Juliana Maria Ferraz, Yu‐Wai‐Man, Patrick, Barsottini, Orlando G.P., and Pedroso, José Luiz

Abstract

Background: ATXN2 is the causative gene of spinocerebellar ataxia type 2 (SCA2) and has been implicated in glaucoma pathogenesis. Therefore, studying ocular changes in SCA2 could uncover clinically relevant changes. Objective: The aim was to investigate optic disc and retinal architecture in SCA2. Methods: We evaluated 14 patients with SCA2 and 26 controls who underwent intraocular pressure measurement, fundoscopy, and macular and peripapillary spectral domain optical coherence tomography (SD‐OCT). We compared SD‐OCT measurements in SCA2 and controls, and the frequency of glaucomatous changes among SCA2, controls, and 76 patients with other SCAs (types 1, 3, 6, and 7). Results: The macula, peripapillary retinal nerve fiber and inner plexiform layers were thinner in SCA2 than in controls. Increased cup‐to‐disc ratio was more frequent in SCA2 than in controls and other SCAs. Conclusions: Ocular changes are part of SCA2 phenotype. Future studies should further investigate retinal and optic nerve architecture in this disorder. [ABSTRACT FROM AUTHOR]

Published
2024
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30. Childhood-Onset Leber Hereditary Optic Neuropathy—Clinical and Prognostic Insights

Author

Barboni, Piero, primary, La Morgia, Chiara, additional, Cascavilla, Maria Lucia, additional, Hong, Eun Hee, additional, Battista, Marco, additional, Majander, Anna, additional, Caporali, Leonardo, additional, Starace, Vincenzo, additional, Amore, Giulia, additional, Renzo, Antonio Di, additional, Carbonelli, Michele, additional, Nucci, Paolo, additional, Jurkute, Neringa, additional, Chen, Benson S., additional, Panebianco, Roberta, additional, De Negri, Anna Maria, additional, Sadun, Federico, additional, Parisi, Vincenzo, additional, Bandello, Francesco, additional, Sadun, Alfredo A., additional, Carelli, Valerio, additional, and Yu-Wai-Man, Patrick, additional

Published
2023
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31. Multidisciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies.

Author

Daich Varela, Malena, Daich Varela, Malena, Bellingham, James, Motta, Fabiana, Jurkute, Neringa, Ellingford, Jamie M, Quinodoz, Mathieu, Oprych, Kathryn, Niblock, Michael, Janeschitz-Kriegl, Lucas, Kaminska, Karolina, Cancellieri, Francesca, Scholl, Hendrik PN, Lenassi, Eva, Schiff, Elena, Knight, Hannah, Black, Graeme, Rivolta, Carlo, Cheetham, Michael E, Michaelides, Michel, Mahroo, Omar A, Moore, Anthony T, Webster, Andrew R, Arno, Gavin, Daich Varela, Malena, Daich Varela, Malena, Bellingham, James, Motta, Fabiana, Jurkute, Neringa, Ellingford, Jamie M, Quinodoz, Mathieu, Oprych, Kathryn, Niblock, Michael, Janeschitz-Kriegl, Lucas, Kaminska, Karolina, Cancellieri, Francesca, Scholl, Hendrik PN, Lenassi, Eva, Schiff, Elena, Knight, Hannah, Black, Graeme, Rivolta, Carlo, Cheetham, Michael E, Michaelides, Michel, Mahroo, Omar A, Moore, Anthony T, Webster, Andrew R, and Arno, Gavin

Abstract

The purpose of this paper is to identify likely pathogenic non-coding variants in inherited retinal dystrophy (IRD) genes, using genome sequencing (GS). Patients with IRD were recruited to the study and underwent comprehensive ophthalmological evaluation and GS. The results of GS were investigated through virtual gene panel analysis, and plausible pathogenic variants and clinical phenotype evaluated by the multidisciplinary team (MDT) discussion. For unsolved patients in whom a specific gene was suspected to harbor a missed pathogenic variant, targeted re-analysis of non-coding regions was performed on GS data. Candidate variants were functionally tested by messenger RNA analysis, minigene or luciferase reporter assays. Previously unreported, likely pathogenic, non-coding variants in 7 genes (PRPF31, NDP, IFT140, CRB1, USH2A, BBS10 and GUCY2D), were identified in 11 patients. These were shown to lead to mis-splicing (PRPF31, IFT140, CRB1 and USH2A) or altered transcription levels (BBS10 and GUCY2D). MDT-led, phenotype-driven, non-coding variant re-analysis of GS is effective in identifying the missing causative alleles.

Published
2023

35. Multidisciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies

Author

Daich Varela, Malena, primary, Bellingham, James, additional, Motta, Fabiana, additional, Jurkute, Neringa, additional, Ellingford, Jamie M, additional, Quinodoz, Mathieu, additional, Oprych, Kathryn, additional, Niblock, Michael, additional, Janeschitz-Kriegl, Lucas, additional, Kaminska, Karolina, additional, Cancellieri, Francesca, additional, Scholl, Hendrik P N, additional, Lenassi, Eva, additional, Schiff, Elena, additional, Knight, Hannah, additional, Black, Graeme, additional, Rivolta, Carlo, additional, Cheetham, Michael E, additional, Michaelides, Michel, additional, Mahroo, Omar A, additional, Moore, Anthony T, additional, Webster, Andrew R, additional, and Arno, Gavin, additional

Published
2022
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36. WFS1-Associated Optic Neuropathy: Genotype-Phenotype Correlations and Disease Progression

Author

Majander, Anna, primary, Jurkute, Neringa, additional, Burté, Florence, additional, Brock, Kristian, additional, João, Catarina, additional, Huang, Houbin, additional, Neveu, Magella M., additional, Chan, Choi Mun, additional, Duncan, Holly J., additional, Kelly, Simon, additional, Burkitt-Wright, Emma, additional, Khoyratty, Fadil, additional, Lai, Yoon Tse, additional, Subash, Mala, additional, Chinnery, Patrick F., additional, Bitner-Glindzicz, Maria, additional, Arno, Gavin, additional, Webster, Andrew R., additional, Moore, Anthony T., additional, Michaelides, Michel, additional, Stockman, Andrew, additional, Robson, Anthony G., additional, and Yu-Wai-Man, Patrick, additional

Published
2022
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38. GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Author

Dixon, Peter H., Levine, Adam P., Cebola, Inês, Chan, Melanie M. Y., Amin, Aliya S., Aich, Anshul, Mozere, Monika, Maude, Hannah, Mitchell, Alice L., Zhang, Jun, Adlard, Julian, Ahmed, Munaza, Aitman, Tim, Alachkar, Hana, Allsup, David, Almeida-King, Jeff, Ancliff, Philip, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Ashford, Sofie, Astle, William, Attwood, Anthony, Babbs, Chris, Bakchoul, Tamam, Bariana, Tadbir, Barwell, Julian, Bennett, David, Bentley, David, Bierzynska, Agnieszka, Biss, Tina, Bleda, Marta, Bogaard, Harm, Bourne, Christian, Boyce, Sara, Bradley, John, Breen, Gerome, Brennan, Paul, Brewer, Carole, Brown, Matthew, Browning, Michael, Buchan, Rachel, Buckland, Matthew, Bueser, Teofila, Burns, Siobhan, Burren, Oliver, Calleja, Paul, Carr-White, Gerald, Carss, Keren, Casey, Ruth, Caulfield, Mark, Chambers, John, Chambers, Jennifer, Cheng, Floria, Chinnery, Patrick F., Christian, Martin, Church, Colin, Brod, Naomi Clements, Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor, Collins, Janine, Collins, Peter, Colombo, Camilla, Condliffe, Robin, Cook, Stuart, Cook, Terry, Cooper, Nichola, Corris, Paul, Crisp-Hihn, Abigail, Curry, Nicola, Danesino, Cesare, Daniels, Matthew, Daugherty, Louise, Davis, John, Deevi, Sri V. V., Dent, Timothy, Dewhurst, Eleanor, Dixon, Peter, Downes, Kate, Drazyk, Anna, Drewe, Elizabeth, Dutt, Tina, Edgar, David, Edwards, Karen, Egner, William, Erber, Wendy, Erwood, Marie, Estiu, Maria C., Evans, Gillian, Evans, Dafydd Gareth, Everington, Tamara, Eyries, Mélanie, Favier, Remi, Fletcher, Debra, Fox, James, Frary, Amy, French, Courtney, Freson, Kathleen, Frontini, Mattia, Gale, Daniel, Gall, Henning, Geoghegan, Claire, Gerighty, Terry, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, Simon, Gilmour, Kimberley, Girerd, Barbara, Goddard, Sarah, Gomez, Keith, Gordins, Pavels, Gosal, David, Gräf, Stefan, Grassi, Luigi, Greene, Daniel, Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip, Grigoriadou, Sofia, Grocock, Russell, Grozeva, Detelina, Hackett, Scott, Hadinnapola, Charaka, Hague, William, Haimel, Matthias, Hall, Matthew, Hanson, Helen, Harkness, Kirsty, Harper, Andrew, Harris, Claire, Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Henderson, Alex, Hoffmann, Jonathan, Horvath, Rita, Houweling, Arjan, Howard, Luke, Hu, Fengyuan, Hudson, Gavin, Hughes, Joseph, Huissoon, Aarnoud, Humbert, Marc, Humphray, Sean, Hunter, Sarah, Hurles, Matthew, Izatt, Louise, James, Roger, Johnson, Sally, Jolles, Stephen, Jolley, Jennifer, Jurkute, Neringa, Kasanicki, Mary, Kazkaz, Hanadi, Kazmi, Rashid, Kelleher, Peter, Kiely, David, Kingston, Nathalie, Klima, Robert, Kostadima, Myrto, Kovacs, Gabor, Koziell, Ania, Kreuzhuber, Roman, Kuijpers, Taco, Kumar, Ajith, Kumararatne, Dinakantha, Kuria, Manju, Laffa, Michael, Lalloo, Fiona, Lamber, Michele, Alle, Hana Lango, Lawrie, Allan, Layton, Mark, Lentaigne, Claire, Levine, Adam, Linger, Rachel, Longhurst, Hilary, Louka, Eleni, Ross, Robert MacKenzie, Madan, Bella, Maher, Eamonn, Maimaris, Jesmeen, Mangles, Sarah, Mapeta, Rutendo, Marchbank, Kevin, Marks, Stephen, Markus, Hugh S., Marshall, Andrew, Martin, Jennifer, Mathias, Mary, Matthews, Emma, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark, Meacham, Stuart, Mead, Adam, Megy, Karyn, Mehta, Sarju, Michaelides, Michel, Millar, Carolyn, Moledina, Shahin, Montani, David, Moor, Tony, Morrell, Nicholas, Muir, Keith, Mumford, Andrew, Newnham, Michael, O'Sullivan, Jennifer, Obaji, Samya, Okoli, Steven, Olschewski, Andrea, Olschewski, Horst, Ong, Kai Ren, Ormondroy, Elizabeth, Ouwehan, Willem, Papadi, Sofia, Park, Soo-Mi, Parry, David, Paterson, Joan, Peacock, Andrew, Peden, John, Peerlinck, Kathelijne, Penkett, Christopher, Pepke-Zaba, Joanna, Petersen, Romina, Pyle, Angela, Rankin, Stuart, Rao, Anupama, Raymond, F. Lucy, Rayner-Matthew, Paula, Rees, Christine, Rendon, Augusto, Renton, Tara, Rice, Andrew, Richardson, Sylvia, Richter, Alex, Roberts, Irene, Roughley, Catherine, Roy, Noemi, Sadeghi-Alavijeh, Omid, Saleem, Moin, Samani, Nilesh, Sanchis-Juan, Alba, Sargur, Ravishankar, Satchell, Simon, Savic, Sinisa, Scelsi, Laura, Schulman, Sol, Scully, Marie, Searle, Claire, Seeger, Werner, Sewell, Carrock, Seyres, Denis, Shapiro, Susie, Sharmardina, Olga, Shtoyerman, Rakefet, Sibson, Keith, Side, Lucy, Simeoni, Ilenia, Simpson, Michael, Sivapalaratnam, Suthesh, Skytte, Anne-Bine, Smith, Katherine, Smith, Kenneth G. C., Snape, Katie, Soubrier, Florent, Staines, Simon, Staples, Emily, Stark, Hannah, Stephens, Jonathan, Stirrups, Kathleen, Stock, Sophie, Suntharalingam, Jay, Swietlik, Emilia, Tait, R. Campbell, Talks, Kate, Tan, Rhea, Thaventhiran, James, Themistocleous, Andreas, Thomas, Moira, Thomson, Kate, Thrasher, Adrian, Thys, Chantal, Tischkowitz, Marc, Titterton, Catherine, Toh, Cheng-Hock, Toshner, Mark, Traylor, Matthew, Treacy, Carmen, Trembath, Richard, Tuna, Salih, Turek, Wojciech, Turro, Ernest, Vale, Tom, Van Geet, Chris, Van Zuydam, Natalie, Vazquez-Lopez, Marta, von Ziegenweidt, Julie, Noordegraaf, Anton Vonk, Waisfisz, Quintin, Walker, Suellen, Ware, James, Watkins, Hugh, Watt, Christopher, Webster, Andrew, Wei, Wei, Welch, Steven, Wessels, Julie, Westbury, Sarah, Westwood, John-Paul, Wharton, John, Whitehorn, Deborah, Whitworth, James, Wilkins, Martin R., Wong, Edwin, Wood, Nicholas, Wood, Yvette, Woods, Geoff, Woodward, Emma, Wort, Stephen, Worth, Austen, Yates, Katherine, Yong, Patrick, Young, Tim, Yu, Ping, Yu-Wai-Man, Patrick, Ambrose, J. C., Arumugam, P., Bevers, R., Bleda, M., Boardman-Pretty, F., Boustred, C. R., Brittain, H., Brown, M. A., Caulfield, M. J., Chan, G. C., Fowler, T., Giess, A., Hamblin, A., Henderson, S., Hubbard, T. J. P., Jackson, R., Jones, L. J., Kasperaviciute, D., Kayikci, M., Kousathanas, A., Lahnstein, L., Leigh, S. E. A., Leong, I. U. S., Lopez, F. J., Maleady-Crowe, F., McEntagart, M., Minneci, F., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A. C., O'Donovan, P., Odhams, C. A., Patch, C., Perez-Gil, D., Pereira, M. B., Pullinger, J., Rahim, T., Rendon, A., Rogers, T., Savage, K., Sawant, K., Scott, R. H., Siddiq, A., Sieghart, A., Smith, S. C., Sosinsky, A., Stuckey, A., Tanguy, M., Taylor Tavares, A. L., Thomas, E. R. A., Thompson, S. R., Tucci, A., Welland, M. J., Williams, E., Witkowska, K., Wood, S. M., Chambers, Jenny, Syngelaki, Argyro, Donnelly, Jennifer, Cooley, Sharon, Geary, Michael, Nicolaides, Kypros, Thorsell, Malin, Hague, William M., Estiu, Maria Cecilia, Marschall, Hanns-Ulrich, Gale, Daniel P., Williamson, Catherine, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, Pediatrics, Foundation for the National Institutes of Health (FNIH), The Academy of Medical Sciences, British Heart Foundation, Imperial College Healthcare NHS Trust- BRC Funding, Paediatric Infectious Diseases / Rheumatology / Immunology, and ARD - Amsterdam Reproduction and Development

Subjects
VARIANT, LOCI, INTEGRATIVE ANALYSIS, General Physics and Astronomy, Cholestasis, Intrahepatic, TRIGLYCERIDE LEVELS, DISEASE, General Biochemistry, Genetics and Molecular Biology, Bile Acids and Salts, Pregnancy, Humans, MUTATION, Science & Technology, Multidisciplinary, Genomics England Research Consortium Collaborators, Infant, Newborn, NIHR BioResource, General Chemistry, GLUCOCORTICOID-RECEPTOR, Multidisciplinary Sciences, ALKALINE SPHINGOMYELINASE, Pregnancy Complications, INSIGHTS, Science & Technology - Other Topics, Premature Birth, Female, FASTING GLUCOSE, Genome-Wide Association Study
Abstract

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5-2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility. ispartof: NATURE COMMUNICATIONS vol:13 issue:1 ispartof: location:England status: published

Published
2022
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39. Pathogenic NR2F1 variants cause a developmental ocular phenotype recapitulated in a mutant mouse model

Author

Jurkute, Neringa, Bertacchi, Michele, Arno, Gavin, Tocco, Chiara, Kim, Ungsoo Samuel, Kruszewski, Adam M, Avery, Robert A, Bedoukian, Emma C, Han, Jinu, Ahn, Sung Jun, Pontikos, Nikolas, Acheson, James, Davagnanam, Indran, Bowman, Richard, Kaliakatsos, Marios, Gardham, Alice, Wakeling, Emma, Oluonye, Ngozi, Reddy, Maddy Ashwin, Clark, Elaine, Rosser, Elisabeth, Amati-Bonneau, Patrizia, Charif, Majida, Lenaers, Guy, Meunier, Isabelle, Defoort, Sabine, Vincent-Delorme, Catherine, Robson, Anthony G, Holder, Graham E, Jeanjean, Luc, Martinez-Monseny, Antonio, Vidal-Santacana, Mariona, Dominici, Chloé, Gaggioli, Cedric, Giordano, Nadia, Caleo, Matteo, Liu, Grant T, Genomics England Research Consortium, Webster, Andrew R, Studer, Michèle, Yu-Wai-Man, Patrick, Jurkute, Neringa [0000-0002-3092-7451], Tocco, Chiara [0000-0002-2616-0198], Han, Jinu [0000-0002-8607-6625], Pontikos, Nikolas [0000-0003-1782-4711], Studer, Michèle [0000-0001-7105-2957], and Apollo - University of Cambridge Repository

Subjects
genetic structures, inherited optic neuropathy, mouse model, BBSOAS, sense organs, eye diseases, optic nerve head anomalies, NR2F1
Abstract

Pathogenic NR2F1 variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic NR2F1 variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously. The visual impairment became apparent in early childhood with small and/or tilted hypoplastic optic nerves observed in 10 cases. High-resolution optical coherence tomography imaging confirmed significant loss of retinal ganglion cells with thinning of the ganglion cell layer, consistent with electrophysiological evidence of retinal ganglion cells dysfunction. Interestingly, for those individuals with available longitudinal ophthalmological data, there was no significant deterioration in visual function during the period of follow-up. Diffusion tensor imaging tractography studies showed defective connections and disorganization of the extracortical visual pathways. To further investigate how pathogenic NR2F1 variants impact on retinal and optic nerve development, we took advantage of an Nr2f1 mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in Nr2f1 mutant mice with decreased retinal ganglion cell density and disruption of retinal ganglion cell axonal guidance from the neural retina into the optic stalk, accounting for the development of optic nerve hypoplasia. The mutant mice showed significantly reduced visual acuity based on electrophysiological parameters with marked conduction delay and decreased amplitude of the recordings in the superficial layers of the visual cortex. The clinical observations in our study cohort, supported by the mouse data, suggest an early neurodevelopmental origin for the retinal and optic nerve head defects caused by NR2F1 pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose NR2F1 as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system.

Published
2021
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40. Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation

Author

Carelli, Valerio, Newman, Nancy J., Yu-Wai-Man, Patrick, Biousse, Valerie, Moster, Mark L., Subramanian, Prem S., Vignal-Clermont, Catherine, Wang, An-Guor, Donahue, Sean P., Leroy, Bart P., Sergott, Robert C., Klopstock, Thomas, Sadun, Alfredo A., Rebolleda Fernández, Gema, Chwalisz, Bart K., Banik, Rudrani, Girmens, Jean François, La Morgia, Chiara, DeBusk, Adam A., Jurkute, Neringa, Priglinger, Claudia, Karanjia, Rustum, Josse, Constant, Salzmann, Julie, Montestruc, François, Roux, Michel, Taiel, Magali, Sahel, José-Alain, Carelli, Valerio, Newman, Nancy J., Yu-Wai-Man, Patrick, Biousse, Valerie, Moster, Mark L., Subramanian, Prem S., Vignal-Clermont, Catherine, Wang, An-Guor, Donahue, Sean P., Leroy, Bart P., Sergott, Robert C., Klopstock, Thomas, Sadun, Alfredo A., Rebolleda Fernández, Gema, Chwalisz, Bart K., Banik, Rudrani, Girmens, Jean François, La Morgia, Chiara, DeBusk, Adam A., Jurkute, Neringa, Priglinger, Claudia, Karanjia, Rustum, Josse, Constant, Salzmann, Julie, Montestruc, François, Roux, Michel, Taiel, Magali, and Sahel, José-Alain

Abstract

INTRODUCTION: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. METHODS: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. RESULTS: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P < 0.01) with a maximal follow-up of 3.9 years after injection. Most treated eyes were on-chart as compared to less than half of natural history eyes at 48 months after vision loss (89.6% versus 48.1%; P < 0.01) and at last observation (76.1% versus 44.4%; P < 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was - 0.43 logMAR (+ 21.5 ETDRS letters equivalent) versus natural history at last observation (P < 0.0001). Treatment effect was consistent across all phase 3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared to unilateral injection. CONCLUSION: The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to the spontaneous natura

Published
2022

42. SSBP1-Disease Update: Expanding the Genetic and Clinical Spectrum, Reporting Variable Penetrance and Confirming Recessive Inheritance

Author

Jurkute, Neringa, D'Esposito, Fabiana, Robson, Anthony G, Pitceathly, Robert DS, Cordeiro, Francesca, Raymond, F Lucy, Moore, Anthony T, Michaelides, Michel, Yu-Wai-Man, Patrick, Webster, Andrew R, Arno, Gavin, Genomics England Research Consortium, Yu Wai Man, Patrick [0000-0001-7847-9320], and Apollo - University of Cambridge Repository

Subjects
Male, Mitochondrial Diseases, Adolescent, Genotyping Techniques, Whole Genome Sequencing, Protein Stability, Molecular Sequence Data, Molecular Conformation, Mutation, Missense, Genes, Recessive, Penetrance, Middle Aged, DNA, Mitochondrial, Pedigree, DNA-Binding Proteins, Mitochondrial Proteins, Optic Atrophy, Child, Preschool, Retinal Dystrophies, Electroretinography, Humans, Female, Amino Acid Sequence, Protein Structure, Quaternary
Abstract

Funder: Wellcome Trust, PURPOSE: To report novel genotypes and expand the phenotype spectrum of SSBP1-disease and explore potential disease mechanism. METHODS: Five families with previously unsolved optic atrophy and retinal dystrophy underwent whole genome sequencing as part of the National Institute for Health Research BioResource Rare-Diseases and the UK's 100,000 Genomes Project. In silico analysis and protein modelling was performed on the identified variants. Deep phenotyping including retinal imaging and International Society for Clinical Electrophysiology of Vision standard visual electrophysiology was performed. RESULTS: Seven individuals from five unrelated families with bilateral optic atrophy and/or retinal dystrophy with extraocular signs and symptoms in some are described. In total, 6 SSBP1 variants were identified including the previously unreported variants: c.151A>G, p.(Lys51Glu), c.335G>A p.(Gly112Glu), and c.380G>A, p.(Arg127Gln). One individual was found to carry biallelic variants (c.380G>A p.(Arg127Gln); c.394A>G p.(Ile132Val)) associated with likely autosomal recessive SSBP1-disease. In silico analysis predicted all variants to be pathogenic and Three-dimensional protein modelling suggested possible disease mechanisms via decreased single-stranded DNA binding affinity or impaired higher structure formation. CONCLUSIONS: SSBP1 is essential for mitochondrial DNA replication and maintenance, with defects leading to a spectrum of disease that includes optic atrophy and/or retinal dystrophy, occurring with or without extraocular features. This study provides evidence of intrafamilial variability and confirms the existence of an autosomal recessive inheritance in SSBP1-disease consequent upon a previously unreported genotype.

Published
2022
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46. Whole-genome sequencing of patients with rare diseases in a national health system

Author

Turro, Ernest, Astle, William J., Megy, Karyn, Gräf, Stefan, Greene, Daniel, Shamardina, Olga, Allen, Hana Lango, Sanchis-Juan, Alba, Frontini, Mattia, Thys, Chantal, Stephens, Jonathan, Mapeta, Rutendo, Burren, Oliver S., Downes, Kate, Haimel, Matthias, Tuna, Salih, Deevi, Sri V.V., Aitman, Timothy J., Bennett, David L., Calleja, Paul, Carss, Keren, Caulfield, Mark J., Chinnery, Patrick F., Dixon, Peter H., Gale, Daniel P., James, Roger, Koziell, Ania, Laffan, Michael A., Levine, Adam P., Maher, Eamonn R., Markus, Hugh S., Morales, Joannella, Morrell, Nicholas W., Mumford, Andrew D., Ormondroyd, Elizabeth, Rankin, Stuart, Rendon, Augusto, Richardson, Sylvia, Roberts, Irene, Roy, Noemi B.A., Saleem, Moin A., Smith, Kenneth G.C., Stark, Hannah, Tan, Rhea Y.Y., Themistocleous, Andreas C., Thrasher, Adrian J., Watkins, Hugh, Webster, Andrew R., Wilkins, Martin R., Williamson, Catherine, Whitworth, James, Humphray, Sean, Bentley, David R., Abbs, Stephen, Abulhoul, Lara, Adlard, Julian, Ahmed, Munaza, Alachkar, Hana, Allsup, David J., Almeida-King, Jeff, Ancliff, Philip, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Ashford, Sofie, Attwood, Anthony, Aurora, Paul, Babbs, Christian, Bacchelli, Chiara, Bakchoul, Tamam, Banka, Siddharth, Bariana, Tadbir, Barwell, Julian, Batista, Joana, Baxendale, Helen E., Beales, Phil L., Bierzynska, Agnieszka, Biss, Tina, Bitner-Glindzicz, Maria A.K., Black, Graeme C., Bleda, Marta, Blesneac, Iulia, Bockenhauer, Detlef, Bogaard, Harm, Bourne, Christian J., Boyce, Sara, Bradley, John R., Bragin, Eugene, Breen, Gerome, Brennan, Paul, Brewer, Carole, Brown, Matthew, Browning, Andrew C., Browning, Michael J., Buchan, Rachel J., Buckland, Matthew S., Bueser, Teofila, Diz, Carmen Bugarin, Burn, John, Burns, Siobhan O., Burrows, Nigel, Campbell, Carolyn, Carr-White, Gerald, Casey, Ruth, Chambers, Jenny, Chambers, John, Chan, Melanie M.Y., Cheah, Calvin, Cheng, Floria, Chitre, Manali, Christian, Martin T., Church, Colin, Clayton-Smith, Jill, Cleary, Maureen, Brod, Naomi Clements, Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor R.P., Collins, Janine, Collins, Peter W., Colombo, Camilla, Compton, Cecilia J., Condliffe, Robin, Cook, Stuart, Cook, H. Terence, Cooper, Nichola, Corris, Paul A A., Furnell, Abigail, Cunningham, Fiona, Curry, Nicola S., Cutler, Antony J., Daniels, Matthew J., Dattani, Mehul, Daugherty, Louise C., Davis, John, De Soyza, Anthony, Dent, Timothy, Deshpande, Charu, Dewhurst, Eleanor F., Douzgou, Sofia, Drazyk, Anna M., Drewe, Elizabeth, Duarte, Daniel, Dutt, Tina, Edgar, J. David M., Edwards, Karen, Egner, William, Ekani, Melanie N., Elliott, Perry, Erber, Wendy N., Erwood, Marie, Estiu, Maria C., Evans, Dafydd Gareth, Evans, Gillian, Everington, Tamara, Eyries, Mélanie, Fassihi, Hiva, Favier, Remi, Findhammer, Jack, Fletcher, Debra, Flinter, Frances A., Floto, R. Andres, Fowler, Tom, Fox, James, Frary, Amy J., French, Courtney E., Freson, Kathleen, Gall, Henning, Ganesan, Vijeya, Gattens, Michael, Geoghegan, Claire, Gerighty, Terence S.A., Gharavi, Ali G., Ghio, Stefano, Ghofrani, Hossein Ardeschir, Gibbs, J. Simon R., Gibson, Kate, Gilmour, Kimberly C., Girerd, Barbara, Gleadall, Nicholas S., Goddard, Sarah, Goldstein, David B., Gomez, Keith, Gordins, Pavels, Gosal, David, Graham, Jodie, Grassi, Luigi, Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip, Grigoriadou, Sofia, Grocock, Russell J., Grozeva, Detelina, Gurnell, Mark, Hackett, Scott, Hadinnapola, Charaka, Hague, William M., Hague, Rosie, Hall, Matthew, Hanson, Helen L., Haque, Eshika, Harkness, Kirsty, Harper, Andrew R., Harris, Claire L L., Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Henderson, Alex, Herwadkar, Archana, Hoffman, Jonathan, Holden, Simon, Horvath, Rita, Houlden, Henry, Houweling, Arjan C C., Howard, Luke S., Hu, Fengyuan, Hudson, Gavin, Hughes, Joseph, Huissoon, Aarnoud P., Humbert, Marc, Hunter, Sarah, Hurles, Matthew, Irving, Melita, Izatt, Louise, Johnson, Sally A., Jolles, Stephen, Jolley, Jennifer, Josifova, Dragana, Jurkute, Neringa, Karten, Tim, Karten, Johannes, Kasanicki, Mary A., Kazkaz, Hanadi, Kazmi, Rashid, Kelleher, Peter, Kelly, Anne M., Kelsall, Wilf, Kempster, Carly, Kiely, David G., Kingston, Nathalie, Klima, Robert, Koelling, Nils, Kostadima, Myrto, Kovacs, Gabor, Kreuzhuber, Roman, Kuijpers, Taco W., Kumar, Ajith, Kumararatne, Dinakantha, Kurian, Manju A., Lalloo, Fiona, Lambert, Michele, Lawrie, Allan, Layton, D. Mark, Lench, Nick, Lentaigne, Claire, Lester, Tracy, Linger, Rachel, Longhurst, Hilary, Lorenzo, Lorena E., Louka, Eleni, Lyons, Paul A., Machado, Rajiv D., MacKenzie Ross, Robert V., Madan, Bella, Maimaris, Jesmeen, Malka, Samantha, Mangles, Sarah, Marchbank, Kevin J., Marks, Stephen, Marschall, Hanns Ulrich, Marshall, Andrew, Martin, Jennifer, Mathias, Mary, Matthews, Emma, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark I., McKinney, Harriet, McMahon, Aoife, Meacham, Stuart, Mead, Adam J., Castello, Ignacio Medina, Mehta, Sarju G G., Michaelides, Michel, Millar, Carolyn, Mohammed, Shehla N., Moledina, Shahin, Montani, David, Moore, Anthony T., Mozere, Monika, Muir, Keith W., Nemeth, Andrea H., Newman, William G., Newnham, Michael, Noorani, Sadia, Nurden, Paquita, O’Sullivan, Jennifer, Obaji, Samya, Odhams, Chris, Okoli, Steven, Olschewski, Andrea, Olschewski, Horst, Ong, Kai Ren, Oram, S. Helen, Ouwehand, Willem H., Palles, Claire, Papadia, Sofia, Park, Soo Mi, Parry, David, Patel, Smita, Paterson, Joan, Peacock, Andrew, Pearce, Simon H H., Peden, John, Peerlinck, Kathelijne, Penkett, Christopher J., Pepke-Zaba, Joanna, Petersen, Romina, Pilkington, Clarissa, Poole, Kenneth E.S., Prathalingam, Radhika, Psaila, Bethan, Pyle, Angela, Quinton, Richard, Rahman, Shamima, Rao, Anupama, Raymond, F. Lucy, Rayner-Matthews, Paula J., Rees, Christine, Renton, Tara, Rhodes, Christopher J., Rice, Andrew S.C., Richter, Alex, Robert, Leema, Rogers, Anthony, Rose, Sarah J., Ross-Russell, Robert, Roughley, Catherine, Roy, Noemi B. A, Ruddy, Deborah M., Sadeghi-Alavijeh, Omid, Samani, Nilesh, Samarghitean, Crina, Sargur, Ravishankar B., Sarkany, Robert N., Satchell, Simon, Savic, Sinisa, Sayer, John A., Sayer, Genevieve, Scelsi, Laura, Schaefer, Andrew M., Schulman, Sol, Scott, Richard, Scully, Marie, Searle, Claire, Seeger, Werner, Sen, Arjune, Sewell, W. A.Carrock, Seyres, Denis, Shah, Neil, Shapiro, Susan E., Shaw, Adam C., Short, Patrick J., Sibson, Keith, Side, Lucy, Simeoni, Ilenia, Simpson, Michael A A., Sims, Matthew C., Sivapalaratnam, Suthesh, Smedley, Damian, Smith, Katherine R., Snape, Katie, Soranzo, Nicole, Soubrier, Florent, Southgate, Laura, Spasic-Boskovic, Olivera, Staines, Simon, Staples, Emily, Steward, Charles, Stirrups, Kathleen E., Stuckey, Alex, Suntharalingam, Jay, Swietlik, Emilia M., Syrris, Petros, Tait, R. Campbell, Talks, Kate, Tate, Katie, Taylor, John M., Taylor, Jenny C., Thaventhiran, James E., Thomas, Ellen, Thomas, David, Thomas, Moira J., Thomas, Patrick, Thomson, Kate, Threadgold, Glen, Tilly, Tobias, Tischkowitz, Marc, Titterton, Catherine, Todd, John A., Toh, Cheng Hock, Tolhuis, Bas, Tomlinson, Ian P., Toshner, Mark, Traylor, Matthew, Treacy, Carmen, Treadaway, Paul, Trembath, Richard, Turek, Wojciech, Twiss, Philip, Vale, Tom, Geet, Chris Van, Zuydam, Natalie van, Vandekuilen, Maarten, Vandersteen, Anthony M., Vazquez-Lopez, Marta, von Ziegenweidt, Julie, Vonk Noordegraaf, Anton, Wagner, Annette, Waisfisz, Quinten, Walker, Suellen M., Walker, Neil, Walter, Klaudia, Ware, James S., Watt, Christopher, Wedderburn, Lucy, Wei, Wei, Welch, Steven B., Wessels, Julie, Westbury, Sarah K., Westwood, John Paul, Wharton, John, Whitehorn, Deborah, Wilkie, Andrew O. M, Wilson, Brian T., Wong, Edwin K.S., Wood, Nicholas, Wood, Yvette, Woods, Christopher Geoffrey, Woodward, Emma R R., Wort, Stephen J., Worth, Austen, Wright, Michael, Yates, Katherine, Yong, Patrick F.K., Young, Timothy, Yu, Ping, Yu-Wai-Man, Patrick, Zlamalova, Eliska, University of Cambridge [UK] (CAM), John Wyeth & Brother Limited, Medical Research Council (MRC), Wellcome Trust, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, Landsteiner Laboratory, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, and Project, NIHR BioResource for the 100,000 Genomes

Subjects
0301 basic medicine, Erythrocytes, Internationality, Databases, Factual, National Health Programs, [SDV]Life Sciences [q-bio], Disease, VARIANTS, Genome, State Medicine, NIHR BioResource for the 100,000 Genomes Project, 0302 clinical medicine, Medicine, GATA1 Transcription Factor, Genetics, Multidisciplinary, Translational bioinformatics, ASSOCIATION, 3. Good health, Multidisciplinary Sciences, Phenotype, 030220 oncology & carcinogenesis, disease genetics, Medical genetics, Science & Technology - Other Topics, Receptors, Thrombopoietin, medicine.medical_specialty, General Science & Technology, Quantitative Trait Loci, Genomics, Computational biology, Biology, DIAGNOSIS, computational biology and bioinformatics, Actin-Related Protein 2-3 Complex, Article, LRBA, LINKS, 03 medical and health sciences, Rare Diseases, Humans, Alleles, Adaptor Proteins, Signal Transducing, Whole genome sequencing, National health, Science & Technology, Whole Genome Sequencing, MUTATIONS, business.industry, THROMBOCYTOPENIA, United Kingdom, MACROTHROMBOCYTOPENIA, genetics research, 030104 developmental biology, business, Rare disease
Abstract

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

Published
2021
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47. Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy

Author

Charif, Majida, Chevrollier, Arnaud, Gueguen, Naïg, Bris, Céline, Goudenège, David, Desquiret-Dumas, Valérie, Leruez, Stéphanie, Colin, Estelle, Meunier, Audrey, Vignal, Catherine, Smirnov, Vasily, Defoort-Dhellemmes, Sabine, Drumare Bouvet, Isabelle, Goizet, Cyril, Votruba, Marcela, Jurkute, Neringa, Yu-Wai-Man, Patrick, Tagliavini, Francesca, Caporali, Leonardo, La Morgia, Chiara, Carelli, Valerio, Procaccio, Vincent, Zanlonghi, Xavier, Meunier, Isabelle, Reynier, Pascal, Bonneau, Dominique, Amati-Bonneau, Patrizia, Lenaers, Guy, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Charif M., Chevrollier A., Gueguen N., Bris C., Goudenege D., Desquiret-Dumas V., Leruez S., Colin E., Meunier A., Vignal C., Smirnov V., Defoort-Dhellemmes S., Drumare Bouvet I., Goizet C., Votruba M., Jurkute N., Yu-Wai-Man P., Tagliavini F., Caporali L., La Morgia C., Carelli V., Procaccio V., Zanlonghi X., Meunier I., Reynier P., Bonneau D., Amati-Bonneau P., Lenaers G., Charif, Majida [0000-0003-3301-4305], Chevrollier, Arnaud [0000-0002-5135-6643], Jurkute, Neringa [0000-0002-3092-7451], Caporali, Leonardo [0000-0002-0666-4380], La Morgia, Chiara [0000-0002-4639-8929], Lenaers, Guy [0000-0003-2736-3349], and Apollo - University of Cambridge Repository

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, genetic structures, [SDV]Life Sciences [q-bio], DOA, 32 Biomedical and Clinical Sciences, Neurodegenerative, SPG7, Article, 3105 Genetics, Rare Diseases, Genetics, 2.1 Biological and endogenous factors, optic atrophy, AFG3L2, Eye Disease and Disorders of Vision, ComputingMilieux_MISCELLANEOUS, 3212 Ophthalmology and Optometry, 2 Aetiology, FOS: Clinical medicine, Neurosciences, eye diseases, Brain Disorders, FOS: Biological sciences, Neurological, sense organs, 31 Biological Sciences
Abstract

Objective To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations.\ud\udMethods Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI.\ud\udResults We identified 7 and 8 new heterozygous pathogenic variants in SPG7 and AFG3L2. Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in AFG3L2 that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the SPG7 variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported.\ud\udConclusions Our results position SPG7 and AFG3L2 as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology.

Published
2020
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48. Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison

Author

Newman, Nancy J., Yu-Wai-Man, Patrick, Carelli, Valerio, Biousse, Valerie, Moster, Mark L., Vignal-Clermont, Catherine, Sergott, Robert C., Klopstock, Thomas, Sadun, Alfredo A., Girmens, Jean-François, La Morgia, Chiara, DeBusk, Adam A., Jurkute, Neringa, Priglinger, Claudia, Karanjia, Rustum, Josse, Constant, Salzmann, Julie, Montestruc, François, Roux, Michel, Taiel, Magali, and Sahel, José-Alain

Subjects
Leber Hereditary Optic Neuropathy, ND4, Gene therapy, Visual acuity, Neurology, genetic structures, Natural history, sense organs, eye diseases
Abstract

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies. Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control. Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss. Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences. Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4. Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of -0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (-0.32 LogMAR, p < 0.0001). Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies. Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.

Published
2021
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50. Clinical and Genetic Findings in CTNNA1-Associated Macular Pattern Dystrophy

Author

Tanner, Alexander, primary, Chan, Hwei Wuen, additional, Pulido, Jose S., additional, Arno, Gavin, additional, Ba-Abbad, Rola, additional, Jurkute, Neringa, additional, Robson, Anthony G., additional, Egan, Catherine A., additional, Knight, Hannah, additional, Calcagni, Antonio, additional, Taylor, Rachel L., additional, Lenassi, Eva, additional, Black, Graeme C., additional, Moore, Anthony T., additional, Michaelides, Michel, additional, Webster, Andrew R., additional, and Mahroo, Omar A., additional

Published
2021
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