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1. IDHwt glioblastomas can be stratified by their transcriptional response to standard treatment, with implications for targeted therapy

Author

Tanner, Georgette, Barrow, Rhiannon, Ajaib, Shoaib, Al-Jabri, Muna, Ahmed, Nazia, Pollock, Steven, Finetti, Martina, Rippaus, Nora, Bruns, Alexander F., Syed, Khaja, Poulter, James A., Matthews, Laura, Hughes, Thomas, Wilson, Erica, Johnson, Colin, Varn, Frederick S., Brüning-Richardson, Anke, Hogg, Catherine, Droop, Alastair, Gusnanto, Arief, Care, Matthew A., Cutillo, Luisa, Westhead, David R., Short, Susan C., Jenkinson, Michael D., Brodbelt, Andrew, Chakrabarty, Aruna, Ismail, Azzam, Verhaak, Roel G. W., and Stead, Lucy F.

Published
2024
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3. A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes

Author

Harris, Erica L., Roy, Vincent, Montagne, Martin, Rose, Ailsa M.S., Livesey, Helen, Reijnders, Margot R.F., Hobson, Emma, Sansbury, Francis H., Willemsen, Marjolein H., Pfundt, Rolph, Warren, Daniel, Long, Vernon, Carr, Ian M., Brunner, Han G., Sheridan, Eamonn G., Firth, Helen V., Lavigne, Pierre, and Poulter, James A.

Published
2024
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4. De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood

Author

Reijnders, Margot R.F., Seibt, Annette, Brugger, Melanie, Lamers, Ideke J.C., Ott, Torsten, Klaas, Oliver, Horváth, Judit, Rose, Ailsa M.S., Craghill, Isabel M., Brunet, Theresa, Graf, Elisabeth, Mayerhanser, Katharina, Hellebrekers, Debby, Pauck, David, Neuen-Jacob, Eva, Rodenburg, Richard J.T., Wieczorek, Dagmar, Klee, Dirk, Mayatepek, Ertan, Driessen, Gertjan, Bindermann, Robert, Averdunk, Luisa, Lohmeier, Klaus, Sinnema, Margje, Stegmann, Alexander P.A., Roepman, Ronald, Poulter, James A., and Distelmaier, Felix

Published
2023
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5. Late-Onset Autosomal Dominant Macular Degeneration Caused by Deletion of the CRX Gene

Author

Ingram, Stuart, Taylor, Rachel, Manson, Forbes, Sergouniotis, Panagiotis, Pontikos, Nikolas, Cheetham, Michael, Fiorentino, Alessia, Downes, Susan, Yu, Jing, Halford, Stephanie, Broadgate, Suzanne, van Heyningen, Veronica, Ambrose, John C., Arumugam, Prabhu, Bevers, Roel, Bleda, Marta, Boardman-Pretty, Freya, Boustred, Christopher R., Brittain, Helen, Caulfield, Mark J., Chan, Georgia C., Elgar, Greg, Fowler, Tom, Giess, Adam, Hamblin, Angela, Henderson, Shirley, Hubbard, Tim J.P., Jackson, Rob, Jones, Louise J., Kasperaviciute, Dalia, Kayikci, Melis, Kousathanas, Athanasios, Lahnstein, Lea, Leigh, Sarah E.A., Leong, Ivonne U.S., Lopez, Javier F., Maleady-Crowe, Fiona, McEntagart, Meriel, Minneci, Federico, Moutsianas, Loukas, Mueller, Michael, Murugaesu, Nirupa, Need, Anna C., O’Donovan, Peter, Odhams, Chris A., Patch, Christine, Pereira, Mariana Buongermino, Perez-Gil, Daniel, Pullinger, John, Rahim, Tahrima, Rendon, Augusto, Rogers, Tim, Savage, Kevin, Sawant, Kushmita, Scott, Richard H., Siddiq, Afshan, Sieghart, Alexander, Smith, Samuel C., Sosinsky, Alona, Stuckey, Alexander, Tanguy, Mélanie, Taylor Tavares, Ana Lisa, Thomas, Ellen R.A., Thompson, Simon R., Tucci, Arianna, Welland, Matthew J., Williams, Eleanor, Witkowska, Katarzyna, Wood, Suzanne M., Yahya, Samar, Smith, Claire E.L., Poulter, James A., McKibbin, Martin, Arno, Gavin, Ellingford, Jamie, Kämpjärvi, Kati, Khan, Muhammad I., Cremers, Frans P.M., Hardcastle, Alison J., Castle, Bruce, Steel, David H.W., Webster, Andrew R., Black, Graeme C., El-Asrag, Mohammed E., Ali, Manir, Toomes, Carmel, and Inglehearn, Chris F.

Published
2023
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6. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis

Author

Ferrada, Marcela A., Savic, Sinisa, Cardona, Daniela Ospina, Collins, Jason C., Alessi, Hugh, Gutierrez-Rodrigues, Fernanda, Kumar, Dinesh Babu Uthaya, Wilson, Lorena, Goodspeed, Wendy, Topilow, James S., Paik, Julie J., Poulter, James A., Kermani, Tanaz A., Koster, Matthew J., Warrington, Kenneth J., Cargo, Catherine, Tattersall, Rachel S., Duncan, Christopher J.A., Cantor, Anna, Hoffmann, Patrycja, Payne, Elspeth M., Bonnekoh, Hanna, Krause, Karoline, Cowen, Edward W., Calvo, Katherine R., Patel, Bhavisha A., Ombrello, Amanda K., Kastner, Daniel L., Young, Neal S., Werner, Achim, Grayson, Peter C., and Beck, David B.

Published
2022
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9. A clinical and molecular characterisation of CRB1-associated maculopathy

Author

Khan, Kamron N, Robson, Anthony, Mahroo, Omar AR, Arno, Gavin, Inglehearn, Chris F, Armengol, Monica, Waseem, Naushin, Holder, Graham E, Carss, Keren J, Raymond, Lucy F, Webster, Andrew R, Moore, Anthony T, McKibbin, Martin, van Genderen, Maria M, Poulter, James A, Michaelides, Michel, and UK Inherited Retinal Disease Consortium

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Clinical Research, Rare Diseases, Neurosciences, Neurodegenerative, Genetics, Eye Disease and Disorders of Vision, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Eye, Adolescent, Adult, Alleles, Child, Child, Preschool, Electronic Health Records, Eye Proteins, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Humans, Infant, Infant, Newborn, Macular Degeneration, Male, Membrane Proteins, Nerve Tissue Proteins, Retinal Photoreceptor Cell Outer Segment, Young Adult, UK Inherited Retinal Disease Consortium, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype-phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull's-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes-intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.

Published
2018

13. DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration

Author

Vig, Anjali, Poulter, James A., Ottaviani, Daniele, Tavares, Erika, Toropova, Katerina, Tracewska, Anna Maria, Mollica, Antonio, Kang, Jasmine, Kehelwathugoda, Oshini, Paton, Tara, Maynes, Jason T., Wheway, Gabrielle, Arno, Gavin, Ambrose, J.C., Arumugam, P., Baple, E.L., Bleda, M., Boardman-Pretty, F., Boissiere, J.M., Boustred, C.R., Brittain, H., Caulfield, M.J., Chan, G.C., Craig, C.E.H., Daugherty, L.C., de Burca, A., Devereau, A., Elgar, G., Foulger, R.E., Fowler, T., Furió-Tarí, P., Hackett, J.M., Halai, D., Hamblin, A., Henderson, S., Holman, J.E., Hubbard, T.J.P., Ibáñez, K., Jackson, R., Jones, L.J., Kasperaviciute, D., Kayikci, M., Lahnstein, L., Lawson, K., Leigh, S.E.A., Leong, I.U.S., Lopez, F.J., Maleady-Crowe, F., Mason, J., McDonagh, E.M., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A.C., Odhams, C.A., Patch, C., Perez-Gil, D., Polychronopoulos, D., Pullinger, J., Rahim, T., Rendon, A., Riesgo-Ferreiro, P., Rogers, T., Ryten, M., Savage, K., Sawant, K., Scott, R.H., Siddiq, A., Sieghart, A., Smedley, D., Smith, K.R., Sosinsky, A., Spooner, W., Stevens, H.E., Stuckey, A., Sultana, R., Thomas, E.R.A., Thompson, S.R., Tregidgo, C., Tucci, A., Walsh, E., Watters, S.A., Welland, M.J., Williams, E., Witkowska, K., Wood, S.M., Zarowiecki, M., Khan, Kamron N., McKibbin, Martin, Toomes, Carmel, Ali, Manir, Di Scipio, Matteo, Li, Shuning, Ellingford, Jamie, Black, Graeme, Webster, Andrew, Rydzanicz, Małgorzata, Stawiński, Piotr, Płoski, Rafał, Vincent, Ajoy, Cheetham, Michael E., Inglehearn, Chris F., Roberts, Anthony, and Heon, Elise

Published
2020
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14. Germline TET2 loss of function causes childhood immunodeficiency and lymphoma

Author

Stremenova Spegarova, Jarmila, Lawless, Dylan, Mohamad, Siti Mardhiana Binti, Engelhardt, Karin R., Doody, Gina, Shrimpton, Jennifer, Rensing-Ehl, Anne, Ehl, Stephan, Rieux-Laucat, Frederic, Cargo, Catherine, Griffin, Helen, Mikulasova, Aneta, Acres, Meghan, Morgan, Neil V., Poulter, James A., Sheridan, Eamonn G., Chetcuti, Philip, O'Riordan, Sean, Anwar, Rashida, Carter, Clive R., Przyborski, Stefan, Windebank, Kevin, Cant, Andrew J., Lako, Majlinda, Bacon, Chris M., Savic, Sinisa, and Hambleton, Sophie

Published
2020
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15. Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

Author

Arno, Gavin, Carss, Keren J, Hull, Sarah, Zihni, Ceniz, Robson, Anthony G, Fiorentino, Alessia, Hardcastle, Alison J, Holder, Graham E, Cheetham, Michael E, Plagnol, Vincent, Moore, Anthony, Raymond, F Lucy, Matter, Karl, Balda, Maria S, Webster, Andrew R, Black, Graeme, Hall, Georgina, Ingram, Stuart, Gillespie, Rachel, Manson, Forbes, Sergouniotis, Panagiotis, Inglehearn, Chris, Toomes, Carmel, Ali, Manir, McKibbin, Martin, Poulter, James, Khan, Kamron, Lord, Emma, Nemeth, Andrea, Downes, Susan, Halford, Stephanie, Yu, Jing, Lise, Stefano, Ponitkos, Nikos, Michaelides, Michel, Webster, Andrew, van Heyningen, Veronica, Aitman, Timothy, Alachkar, Hana, Ali, Sonia, Allen, Louise, Allsup, David, Ambegaonkar, Gautum, Anderson, Julie, Antrobus, Richard, Armstrong, Ruth, Arumugakani, Gururaj, Ashford, Sofie, Astle, William, Attwood, Antony, Austin, Steve, Bacchelli, Chiara, Bakchoul, Tamam, Bariana, Tadbir K, Baxendale, Helen, Bennett, David, Bethune, Claire, Bibi, Shahnaz, Bitner-Glindzicz, Maria, Bleda, Marta, Boggard, Harm, Bolton-Maggs, Paula, Booth, Claire, Bradley, John R, Brady, Angie, Brown, Matthew, Browning, Michael, Bryson, Christine, Burns, Siobhan, Calleja, Paul, Canham, Natalie, Carmichael, Jenny, Carss, Keren, Caulfield, Mark, Chalmers, Elizabeth, Chandra, Anita, Chinnery, Patrick, Chitre, Manali, Church, Colin, Clement, Emma, Clements-Brod, Naomi, Clowes, Virginia, Coghlan, Gerry, Collins, Peter, Cooper, Nichola, Creaser-Myers, Amanda, DaCosta, Rosa, Daugherty, Louise, Davies, Sophie, Davis, John, De Vries, Minka, Deegan, Patrick, Deevi, Sri VV, and Deshpande, Charu

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Ophthalmology and Optometry, Human Genome, Rare Diseases, Neurosciences, Eye Disease and Disorders of Vision, Aetiology, 2.1 Biological and endogenous factors, Eye, Adult, Alleles, Amino Acid Sequence, Cell Polarity, Epithelial Cells, Exome, Eye Proteins, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Male, Membrane Proteins, Middle Aged, Mutation, Missense, Nerve Tissue Proteins, Pedigree, Phenotype, Retina, Retinal Degeneration, Retinal Dystrophies, Rho Guanine Nucleotide Exchange Factors, rhoA GTP-Binding Protein, UK Inherited Retinal Disease Consortium, NIHR Bioresource - Rare Diseases Consortium, ARHGEF18, apicobasal polarity, inherited retinal dystrophy, p114RhoGEF, retinal degeneration, retinitis pigmentosa, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs∗63), c.1996C>T (p.Arg666∗), c.2632G>T (p.Glu878∗), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.

Published
2017

16. Biallelic mutations in SUPV3L1 cause an inherited neurodevelopmental disorder with variable leukodystrophy due to aberrant mitochondrial double stranded RNA processing

Author

Green, Lydia, primary, Hamilton, Noémie, additional, Elpidorou, Marilena, additional, Maroofian, Reza, additional, Douglas, Andrew G.L., additional, Õunap, Katrin, additional, Rose, Ailsa M.S., additional, Harris, Erica L., additional, Elworthy, Stone, additional, Renshaw, Stephen A., additional, Low, Elizabeth C., additional, Dockrell, David H., additional, Tveten, Kristian, additional, Wells, Geoffrey, additional, Harris, Sarah A., additional, Al-Maawali, Almundher, additional, Al-Thihli, Khalid, additional, Al-Zuhaibi, Sana, additional, Futaisi, Amna Al, additional, Calame, Daniel, additional, Chinn, Ivan, additional, Fisher, Kristen S., additional, Sa, Mario, additional, Warren, Daniel, additional, Zamani, Mina, additional, Sadeghian, Saeid, additional, Azizimalamiri, Reza, additional, Galehdari, Hamid, additional, Shariati, Gholamreza, additional, Seifi, Tahere, additional, Zaki, Maha S., additional, Afzal, Erum, additional, Tarnopolsky, Mark A., additional, Brady, Lauren, additional, Zuchner, Stephan L., additional, Efthymiou, Stephanie, additional, Scardamaglia, Annarita, additional, Houlden, Henry, additional, Wakeling, Emma, additional, Prabhakar, Prab, additional, Roca-Bayerri, Carla, additional, Rice, Gillian I., additional, Prouteau, Clément, additional, Bris, Céline, additional, Tessarech, Marine, additional, Sandvig, Inger, additional, Sheridan, Eamonn G., additional, Johnson, Colin A., additional, Livingston, John H., additional, Crow, Yanick J., additional, and Poulter, James A., additional

Published
2024
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17. Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa

Author

Arno, Gavin, Agrawal, Smriti A, Eblimit, Aiden, Bellingham, James, Xu, Mingchu, Wang, Feng, Chakarova, Christina, Parfitt, David A, Lane, Amelia, Burgoyne, Thomas, Hull, Sarah, Carss, Keren J, Fiorentino, Alessia, Hayes, Matthew J, Munro, Peter M, Nicols, Ralph, Pontikos, Nikolas, Holder, Graham E, UKIRDC, Black, Graeme, Hall, Georgina, Ingram, Stuart, Gillespie, Rachel, Manson, Forbes, Sergouniotis, Panagiotis, Inglehearn, Chris, Toomes, Carmel, Ali, Manir, McKibbin, Martin, Poulter, James, Khan, Kamron, Lord, Emma, Nemeth, Andrea, Downes, Susan, Yu, Jing, Lise, Stefano, Ponitkos, Nikos, Plagnol, Vincent, Michaelides, Michel, Hardcastle, Alison J, Cheetham, Michael E, Webster, Andrew R, van Heyningen, Veronica, Asomugha, Chinwe, Raymond, F Lucy, Moore, Anthony T, Li, Yumei, Cukras, Catherine, and Chen, Rui

Subjects
Genetics, Biotechnology, Neurodegenerative, Rare Diseases, Clinical Research, Eye Disease and Disorders of Vision, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Eye, Adolescent, Alleles, Animals, Child, Child, Preschool, Eye Proteins, Female, Genes, Recessive, Humans, Induced Pluripotent Stem Cells, Male, Membrane Proteins, Membrane Transport Proteins, Mice, Mutation, Mutation, Missense, Phenotype, Photoreceptor Cells, Vertebrate, Retinitis Pigmentosa, Young Adult, UKIRDC, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy. RP is genetically heterogeneous and the genes identified to date encode proteins involved in a wide range of functional pathways, including photoreceptor development, phototransduction, the retinoid cycle, cilia, and outer segment development. Here we report the identification of biallelic mutations in Receptor Expression Enhancer Protein 6 (REEP6) in seven individuals with autosomal-recessive RP from five unrelated families. REEP6 is a member of the REEP/Yop1 family of proteins that influence the structure of the endoplasmic reticulum but is relatively unstudied. The six variants identified include three frameshift variants, two missense variants, and a genomic rearrangement that disrupts exon 1. Human 3D organoid optic cups were used to investigate REEP6 expression and confirmed the expression of a retina-specific isoform REEP6.1, which is specifically affected by one of the frameshift mutations. Expression of the two missense variants (c.383C>T [p.Pro128Leu] and c.404T>C [p.Leu135Pro]) and the REEP6.1 frameshift mutant in cultured cells suggest that these changes destabilize the protein. Furthermore, CRISPR-Cas9-mediated gene editing was used to produce Reep6 knock-in mice with the p.Leu135Pro RP-associated variant identified in one RP-affected individual. The homozygous knock-in mice mimic the clinical phenotypes of RP, including progressive photoreceptor degeneration and dysfunction of the rod photoreceptors. Therefore, our study implicates REEP6 in retinal homeostasis and highlights a pathway previously uncharacterized in retinal dystrophy.

Published
2016

19. Loss-of-Function Mutations in the CFH Gene Affecting Alternatively Encoded Factor H-like 1 Protein Cause Dominant Early-Onset Macular Drusen

Author

Black, Graeme, Hall, Georgina, Ingram, Stuart, Taylor, Rachel, Manson, Forbes, Sergouniotis, Panagiotis, Webster, Andrew, Hardcastle, Alison, Michaelides, Michel, Plagnol, Vincent, Pontikos, Nikolas, Cheetham, Michael, Arno, Gavin, Fiorentino, Alessia, Inglehearn, Chris, Toomes, Carmel, Ali, Manir, McKibbin, Martin, Smith, Claire, Khan, Kamron, Downes, Susan, Yu, Jing, Halford, Stephanie, Broadgate, Suzanne, van Heyningen, Veronica, Taylor, Rachel L., Poulter, James A., Downes, Susan M., Khan, Kamron N., Inglehearn, Chris F., Webster, Andrew R., Hardcastle, Alison J., Bishop, Paul N., Clark, Simon J., and Black, Graeme C.

Published
2019
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20. Biallelic variants in Plexin B2 (PLXNB2) cause amelogenesis imperfecta, hearing loss and intellectual disability.

Author

Smith, Claire E. L., Laugel-Haushalter, Virginie, Hany, Ummey, Best, Sunayna, Taylor, Rachel L., Poulter, James A., Wortmann, Saskia B., Feichtinger, Rene G., Mayr, Johannes A., Al Bahlani, Suhaila, Nikolopoulos, Georgios, Rigby, Alice, Black, Graeme C., Watson, Christopher M., Mansour, Sahar, Inglehearn, Chris F., Mighell, Alan J., and Bloch-Zupan, Agnès

Abstract

Background Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic PLXND1 and PLXNA1 variants have so far been associated with Mendelian genetic disease. Methods Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice. Results Rare biallelic pathogenic variants in plexin B2 (PLXNB2), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. Plxnb2 expression was detected in differentiating ameloblasts. Conclusion We identify rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in Plxnb2 knockout mice, and, together with the rarity of human PLXNB2 variants, may explain why pathogenic variants in PLXNB2 have not been reported previously. [ABSTRACT FROM AUTHOR]

Published
2024
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21. Biallelic Mutations in LRRC56, Encoding a Protein Associated with Intraflagellar Transport, Cause Mucociliary Clearance and Laterality Defects

Author

Bonnefoy, Serge, Watson, Christopher M., Kernohan, Kristin D., Lemos, Moara, Hutchinson, Sebastian, Poulter, James A., Crinnion, Laura A., Berry, Ian, Simmonds, Jennifer, Vasudevan, Pradeep, O’Callaghan, Chris, Hirst, Robert A., Rutman, Andrew, Huang, Lijia, Hartley, Taila, Grynspan, David, Moya, Eduardo, Li, Chunmei, Carr, Ian M., Bonthron, David T., Leroux, Michel, Boycott, Kym M., Bastin, Philippe, and Sheridan, Eamonn G.

Published
2018
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22. Recessive Mutations in SLC38A8 Cause Foveal Hypoplasia and Optic Nerve Misrouting without Albinism

Author

Poulter, James A, Al-Araimi, Musallam, Conte, Ivan, van Genderen, Maria M, Sheridan, Eamonn, Carr, Ian M, Parry, David A, Shires, Mike, Carrella, Sabrina, Bradbury, John, Khan, Kamron, Lakeman, Phillis, Sergouniotis, Panagiotis I, Webster, Andrew R, Moore, Anthony T, Pal, Bishwanath, Mohamed, Moin D, Venkataramana, Anandula, Ramprasad, Vedam, Shetty, Rohit, Saktivel, Murugan, Kumaramanickavel, Govindasamy, Tan, Alex, Mackey, David A, Hewitt, Alex W, Banfi, Sandro, Ali, Manir, Inglehearn, Chris F, and Toomes, Carmel

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Eye Disease and Disorders of Vision, Pediatric, Neurosciences, Congenital Structural Anomalies, Clinical Research, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Albinism, Amino Acid Transport Systems, Neutral, Animals, Child, Consanguinity, DNA Mutational Analysis, Female, Fovea Centralis, Genes, Recessive, Homozygote, Humans, Male, Mutation, Optic Nerve, Pedigree, Phenotype, Syndrome, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Foveal hypoplasia and optic nerve misrouting are developmental defects of the visual pathway and only co-occur in connection with albinism; to date, they have only been associated with defects in the melanin-biosynthesis pathway. Here, we report that these defects can occur independently of albinism in people with recessive mutations in the putative glutamine transporter gene SLC38A8. Nine different mutations were identified in seven Asian and European families. Using morpholino-mediated ablation of Slc38a8 in medaka fish, we confirmed that pigmentation is unaffected by loss of SLC38A8. Furthermore, by undertaking an association study with SNPs at the SLC38A8 locus, we showed that common variants within this gene modestly affect foveal thickness in the general population. This study reveals a melanin-independent component underpinning the development of the visual pathway that requires a functional role for SLC38A8.

Published
2013

23. HeterozygousCOL17A1variants are a frequent cause of amelogenesis imperfecta

Author

Hany, Ummey, primary, Watson, Christopher M, additional, Liu, Lu, additional, Smith, Claire E L, additional, Harfoush, Asmaa, additional, Poulter, James A, additional, Nikolopoulos, Georgios, additional, Balmer, Richard, additional, Brown, Catriona J, additional, Patel, Anesha, additional, Simmonds, Jenny, additional, Charlton, Ruth, additional, Acosta de Camargo, María Gabriela, additional, Rodd, Helen D, additional, Jafri, Hussain, additional, Antanaviciute, Agne, additional, Moffat, Michelle, additional, Al-Jawad, Maisoon, additional, Inglehearn, Chris F, additional, and Mighell, Alan J, additional

Published
2023
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25. Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies

Author

Black, Graeme, Hall, Georgina, Gillespie, Rachel, Ramsden, Simon, Manson, Forbes, Sergouniotis, Panagiotis, Inglehearn, Chris, Toomes, Carmel, Ali, Manir, McKibbin, Martin, Poulter, James, Lord, Emma, Nemeth, Andrea, Halford, Stephanie, Downes, Susan, Yu, Jing, Xu, Mingchu, Xie, Yajing (Angela), Abouzeid, Hana, Gordon, Christopher T., Fiorentino, Alessia, Sun, Zixi, Lehman, Anna, Osman, Ihab S., Dharmat, Rachayata, Riveiro-Alvarez, Rosa, Bapst-Wicht, Linda, Babino, Darwin, Arno, Gavin, Busetto, Virginia, Zhao, Li, Li, Hui, Lopez-Martinez, Miguel A., Azevedo, Liliana F., Hubert, Laurence, Pontikos, Nikolas, Eblimit, Aiden, Lorda-Sanchez, Isabel, Kheir, Valeria, Plagnol, Vincent, Oufadem, Myriam, Soens, Zachry T., Yang, Lizhu, Bole-Feysot, Christine, Pfundt, Rolph, Allaman-Pillet, Nathalie, Nitschké, Patrick, Cheetham, Michael E., Lyonnet, Stanislas, Agrawal, Smriti A., Li, Huajin, Pinton, Gaëtan, Michaelides, Michel, Besmond, Claude, Li, Yumei, Yuan, Zhisheng, von Lintig, Johannes, Webster, Andrew R., Le Hir, Hervé, Stoilov, Peter, Amiel, Jeanne, Hardcastle, Alison J., Ayuso, Carmen, Sui, Ruifang, Chen, Rui, Allikmets, Rando, and Schorderet, Daniel F.

Published
2017
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26. Heterozygous COL17A1 variants are a frequent cause of amelogenesis imperfecta.

Author

Hany, Ummey, Watson, Christopher M., Lu Liu, Smith, Claire E. L., Harfoush, Asmaa, Poulter, James A., Nikolopoulos, Georgios, Balmer, Richard, Brown, Catriona J., Pate, Anesha, Simmonds, Jenny, Charlton, Ruth, Acosta de Camargo, María Gabriela, Rodd, Helen D., Jafri, Hussain, Antanaviciute, Agne, Moffat, Michelle, Al-Jawad, Maisoon, Inglehearn, Chris F., and Mighell, Alan J.

Abstract

Background Collagen XVII is most typically associated with human disease when biallelic COL17A1 variants (>230) cause junctional epidermolysis bullosa (JEB), a rare, genetically heterogeneous, mucocutaneous blistering disease with amelogenesis imperfecta (AI), a developmental enamel defect. Despite recognition that heterozygous carriers in JEB families can have AI, and that heterozygous COL17A1 variants also cause dominant corneal epithelial recurrent erosion dystrophy (ERED), the importance of heterozygous COL17A1 variants causing dominant non-syndromic AI is not widely recognised. Methods Probands from an AI cohort were screened by single molecule molecular inversion probes or targeted hybridisation capture (both a custom panel and whole exome sequencing) for COL17A1 variants. Patient phenotypes were assessed by clinical examination and analyses of affected teeth. Results Nineteen unrelated probands with isolated AI (no co-segregating features) had 17 heterozygous, potentially pathogenic COL17A1 variants, including missense, premature termination codons, frameshift and splice site variants in both the endo-domains and the ecto-domains of the protein. The AI phenotype was consistent with enamel of near normal thickness and variable focal hypoplasia with surface irregularities including pitting. Conclusion These results indicate that COL17A1 variants are a frequent cause of dominantly inherited non-syndromic AI. Comparison of variants implicated in AI and JEB identifies similarities in type and distribution, with five identified in both conditions, one of which may also cause ERED. Increased availability of genetic testing means that more individuals will receive reports of heterozygous COL17A1 variants. We propose that patients with isolated AI or ERED, due to COL17A1 variants, should be considered as potential carriers for JEB and counselled accordingly, reflecting the importance of multidisciplinary care. [ABSTRACT FROM AUTHOR]

Published
2024
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28. WITHDRAWN: Biallelic mutation ofSUPV3L1causes an inherited leukodystrophy-associated neurodevelopmental disorder due to aberrant mitochondrial double stranded RNA processing

Author

Green, Lydia, primary, Hamilton, Noémie, additional, Elpidorou, Marilena, additional, Harris, Erica L., additional, Douglas, Andrew, additional, Ounap, Katrin, additional, Maroofian, Reza, additional, Rose, Ailsa M.S., additional, Elworthy, Stone, additional, Renshaw, Stephen A, additional, Low, Elizabeth C., additional, Prescott, Trine, additional, Soberg, Kristoffer, additional, Al-Maawali, Almunder, additional, Al-Zuhaibi, Sana, additional, Futaisi, Amna Al, additional, Calame, Daniel, additional, Al-Thihli, Khalid, additional, Sheridan, Eamonn G., additional, Johnson, Colin A., additional, Livingston, John, additional, Crow, Yanick J., additional, and Poulter, James A, additional

Published
2023
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29. A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.

Author

Harris, Erica, primary, Roy, Vincent, additional, Montagne, Martin, additional, Rose, Ailsa, additional, Livesey, Helen, additional, Hobson, Emma, additional, Warren, Daniel, additional, Long, Vernon, additional, Sheridan, Eamonn, additional, Reijnders, Margot, additional, Sansbury, Francis, additional, Willemsen, Marjolein, additional, Pfundt, Rolph, additional, Brunner, Han, additional, Carr, Ian, additional, Firth, Helen, additional, Lavigne, Pierre, additional, and Poulter, James, additional

Published
2023
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30. Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa

Author

Black, Graeme, Hall, Georgina, Ingram, Stuart, Gillespie, Rachel, Manson, Forbes, Sergouniotis, Panagiotis, Inglehearn, Chris, Toomes, Carmel, Ali, Manir, McKibbin, Martin, Poulter, James, Khan, Kamron, Lord, Emma, Nemeth, Andrea, Downes, Susan, Yu, Jing, Lise, Stefano, Arno, Gavin, Fiorentino, Alessia, Ponitkos, Nikos, Plagnol, Vincent, Michaelides, Michel, Hardcastle, Alison J., Cheetham, Michael E., Webster, Andrew R., van Heyningen, Veronica, Agrawal, Smriti A., Eblimit, Aiden, Bellingham, James, Xu, Mingchu, Wang, Feng, Chakarova, Christina, Parfitt, David A., Lane, Amelia, Burgoyne, Thomas, Hull, Sarah, Carss, Keren J., Hayes, Matthew J., Munro, Peter M., Nicols, Ralph, Pontikos, Nikolas, Holder, Graham E., Asomugha, Chinwe, Raymond, F. Lucy, Moore, Anthony T., Li, Yumei, Cukras, Catherine, and Chen, Rui

Published
2016
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31. Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis

Author

Novartis, Foundation Fighting Blindness, Ghent University, Research Foundation - Flanders, European Commission, Panneman, Daan M., Hitti-Malin, Rebekkah J., Holtes, Lara K., Bruijn, Suzanne E. de, Reurink, Janine, Boonen, Erica G. M., Khan, Muhammad Imran, Ali, Manir, Andréasson, Sten, De Baere, Elfride, Banfi, Sandro, Bauwens, Miriam, Ben-Yosef, Tamar, Bocquet, Béatrice, De Bruyne, Marieke, Cerda, Berta de la, Coppieters, Frauke, Farinelli, Pietro, Guignard, Thomas, Inglehearn, Chris F., Karali, Marianthi, Kjellström, Ulrika, Koenekoop, Robert, Koning, Bart de, Leroy, Bart P., McKibbin, Martin, Meunier, Isabelle, Nikopoulos, Konstantinos, Nishiguchi, Koji M., Poulter, James A., Rivolta, Carlo, Rodríguez de la Rúa, Enrique, Saunders, Patrick, Simonelli, Francesca, Tatour, Yasmin, Testa, Francesco, Thiadens, Alberta A. H. J., Toomes, Carmel, Tracewska, Anna M., Tran, Hoai Viet, Ushida, Hiroaki, Vaclavik, Veronika, Verhoeven, Virginie J. M., Vorst, Maartje van de, Gilissen, Christian, Hoischen, Alexander, Cremers, Frans P. M., Roosing, Susanne, Novartis, Foundation Fighting Blindness, Ghent University, Research Foundation - Flanders, European Commission, Panneman, Daan M., Hitti-Malin, Rebekkah J., Holtes, Lara K., Bruijn, Suzanne E. de, Reurink, Janine, Boonen, Erica G. M., Khan, Muhammad Imran, Ali, Manir, Andréasson, Sten, De Baere, Elfride, Banfi, Sandro, Bauwens, Miriam, Ben-Yosef, Tamar, Bocquet, Béatrice, De Bruyne, Marieke, Cerda, Berta de la, Coppieters, Frauke, Farinelli, Pietro, Guignard, Thomas, Inglehearn, Chris F., Karali, Marianthi, Kjellström, Ulrika, Koenekoop, Robert, Koning, Bart de, Leroy, Bart P., McKibbin, Martin, Meunier, Isabelle, Nikopoulos, Konstantinos, Nishiguchi, Koji M., Poulter, James A., Rivolta, Carlo, Rodríguez de la Rúa, Enrique, Saunders, Patrick, Simonelli, Francesca, Tatour, Yasmin, Testa, Francesco, Thiadens, Alberta A. H. J., Toomes, Carmel, Tracewska, Anna M., Tran, Hoai Viet, Ushida, Hiroaki, Vaclavik, Veronika, Verhoeven, Virginie J. M., Vorst, Maartje van de, Gilissen, Christian, Hoischen, Alexander, Cremers, Frans P. M., and Roosing, Susanne

Abstract

Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies. Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases. Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.

Published
2023

32. Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis

Author

Panneman, Daan M., Hitti-Malin, Rebekkah J., Holtes, Lara K., de Bruijn, Suzanne E., Reurink, Janine, Boonen, Erica G.M., Khan, Muhammad Imran, Ali, Manir, Andréasson, Sten, De Baere, Elfride, Banfi, Sandro, Bauwens, Miriam, Ben-Yosef, Tamar, Bocquet, Béatrice, De Bruyne, Marieke, Cerda, Berta de la, Coppieters, Frauke, Farinelli, Pietro, Guignard, Thomas, Inglehearn, Chris F., Karali, Marianthi, Kjellström, Ulrika, Koenekoop, Robert, de Koning, Bart, Leroy, Bart P., McKibbin, Martin, Meunier, Isabelle, Nikopoulos, Konstantinos, Nishiguchi, Koji M., Poulter, James A., Rivolta, Carlo, Rodríguez de la Rúa, Enrique, Saunders, Patrick, Simonelli, Francesca, Tatour, Yasmin, Testa, Francesco, Thiadens, Alberta A.H.J., Toomes, Carmel, Tracewska, Anna M., Tran, Hoai Viet, Ushida, Hiroaki, Vaclavik, Veronika, Verhoeven, Virginie J.M., van de Vorst, Maartje, Gilissen, Christian, Hoischen, Alexander, Cremers, Frans P.M., Roosing, Susanne, Panneman, Daan M., Hitti-Malin, Rebekkah J., Holtes, Lara K., de Bruijn, Suzanne E., Reurink, Janine, Boonen, Erica G.M., Khan, Muhammad Imran, Ali, Manir, Andréasson, Sten, De Baere, Elfride, Banfi, Sandro, Bauwens, Miriam, Ben-Yosef, Tamar, Bocquet, Béatrice, De Bruyne, Marieke, Cerda, Berta de la, Coppieters, Frauke, Farinelli, Pietro, Guignard, Thomas, Inglehearn, Chris F., Karali, Marianthi, Kjellström, Ulrika, Koenekoop, Robert, de Koning, Bart, Leroy, Bart P., McKibbin, Martin, Meunier, Isabelle, Nikopoulos, Konstantinos, Nishiguchi, Koji M., Poulter, James A., Rivolta, Carlo, Rodríguez de la Rúa, Enrique, Saunders, Patrick, Simonelli, Francesca, Tatour, Yasmin, Testa, Francesco, Thiadens, Alberta A.H.J., Toomes, Carmel, Tracewska, Anna M., Tran, Hoai Viet, Ushida, Hiroaki, Vaclavik, Veronika, Verhoeven, Virginie J.M., van de Vorst, Maartje, Gilissen, Christian, Hoischen, Alexander, Cremers, Frans P.M., and Roosing, Susanne

Abstract

Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies. Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases. Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.

Published
2023

33. Targeted nanopore sequencing enables complete characterisation of structural deletions initially identified using exon‐based short‐read sequencing strategies

Author

McClinton, Benjamin, primary, Crinnion, Laura A., additional, McKibbin, Martin, additional, Mukherjee, Rajarshi, additional, Poulter, James A., additional, Smith, Claire E. L., additional, Ali, Manir, additional, Watson, Christopher M., additional, Inglehearn, Chris F., additional, and Toomes, Carmel, additional

Published
2023
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34. Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6

Author

Ratbi, Ilham, Falkenberg, Kim D., Sommen, Manou, Al-Sheqaih, Nada, Guaoua, Soukaina, Vandeweyer, Geert, Urquhart, Jill E., Chandler, Kate E., Williams, Simon G., Roberts, Neil A., El Alloussi, Mustapha, Black, Graeme C., Ferdinandusse, Sacha, Ramdi, Hind, Heimler, Audrey, Fryer, Alan, Lynch, Sally-Ann, Cooper, Nicola, Ong, Kai Ren, Smith, Claire E.L., Inglehearn, Christopher F., Mighell, Alan J., Elcock, Claire, Poulter, James A., Tischkowitz, Marc, Davies, Sally J., Sefiani, Abdelaziz, Mironov, Aleksandr A., Newman, William G., Waterham, Hans R., and Van Camp, Guy

Published
2015
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35. IDHwt glioblastomas can be stratified by their transcriptional response to standard treatment, with implications for targeted therapy

Author

Tanner, Georgette, primary, Barrow, Rhiannon, additional, Finetti, Martina, additional, Ajaib, Shoaib, additional, Ahmed, Nazia, additional, Pollock, Steven, additional, Rippaus, Nora, additional, Bruns, Alexander F., additional, Syed, Khaja, additional, Poulter, James, additional, Wilson, Erica, additional, Johnson, Colin, additional, Varn, Frederick S., additional, Brüning-Richardson, Anke, additional, Hogg, Catherine, additional, Droop, Alastair, additional, Gusnanto, Arief, additional, Care, Matthew A., additional, Cutillo, Luisa, additional, Westhead, David, additional, Short, Susan C., additional, Jenkinson, Michael D., additional, Brodbelt, Andrew, additional, Chakrabarty, Aruna, additional, Ismail, Azzam, additional, Verhaak, Roel GW, additional, and Stead, Lucy F., additional

Published
2023
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36. Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis

Author

Panneman, Daan M., primary, Hitti-Malin, Rebekkah J., additional, Holtes, Lara K., additional, de Bruijn, Suzanne E., additional, Reurink, Janine, additional, Boonen, Erica G. M., additional, Khan, Muhammad Imran, additional, Ali, Manir, additional, Andréasson, Sten, additional, De Baere, Elfride, additional, Banfi, Sandro, additional, Bauwens, Miriam, additional, Ben-Yosef, Tamar, additional, Bocquet, Béatrice, additional, De Bruyne, Marieke, additional, Cerda, Berta de la, additional, Coppieters, Frauke, additional, Farinelli, Pietro, additional, Guignard, Thomas, additional, Inglehearn, Chris F., additional, Karali, Marianthi, additional, Kjellström, Ulrika, additional, Koenekoop, Robert, additional, de Koning, Bart, additional, Leroy, Bart P., additional, McKibbin, Martin, additional, Meunier, Isabelle, additional, Nikopoulos, Konstantinos, additional, Nishiguchi, Koji M., additional, Poulter, James A., additional, Rivolta, Carlo, additional, Rodríguez de la Rúa, Enrique, additional, Saunders, Patrick, additional, Simonelli, Francesca, additional, Tatour, Yasmin, additional, Testa, Francesco, additional, Thiadens, Alberta A. H. J., additional, Toomes, Carmel, additional, Tracewska, Anna M., additional, Tran, Hoai Viet, additional, Ushida, Hiroaki, additional, Vaclavik, Veronika, additional, Verhoeven, Virginie J. M., additional, van de Vorst, Maartje, additional, Gilissen, Christian, additional, Hoischen, Alexander, additional, Cremers, Frans P. M., additional, and Roosing, Susanne, additional

Published
2023
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37. Late-Onset Autosomal Dominant Macular Degeneration Caused by Deletion of the CRX Gene

Author

Yahya, Samar, primary, Smith, Claire E.L., additional, Poulter, James A., additional, McKibbin, Martin, additional, Arno, Gavin, additional, Ellingford, Jamie, additional, Kämpjärvi, Kati, additional, Khan, Muhammad I., additional, Cremers, Frans P.M., additional, Hardcastle, Alison J., additional, Castle, Bruce, additional, Steel, David H.W., additional, Webster, Andrew R., additional, Black, Graeme C., additional, El-Asrag, Mohammed E., additional, Ali, Manir, additional, Toomes, Carmel, additional, Inglehearn, Chris F., additional, Ingram, Stuart, additional, Taylor, Rachel, additional, Manson, Forbes, additional, Sergouniotis, Panagiotis, additional, Pontikos, Nikolas, additional, Cheetham, Michael, additional, Fiorentino, Alessia, additional, Downes, Susan, additional, Yu, Jing, additional, Halford, Stephanie, additional, Broadgate, Suzanne, additional, van Heyningen, Veronica, additional, Ambrose, John C., additional, Arumugam, Prabhu, additional, Bevers, Roel, additional, Bleda, Marta, additional, Boardman-Pretty, Freya, additional, Boustred, Christopher R., additional, Brittain, Helen, additional, Caulfield, Mark J., additional, Chan, Georgia C., additional, Elgar, Greg, additional, Fowler, Tom, additional, Giess, Adam, additional, Hamblin, Angela, additional, Henderson, Shirley, additional, Hubbard, Tim J.P., additional, Jackson, Rob, additional, Jones, Louise J., additional, Kasperaviciute, Dalia, additional, Kayikci, Melis, additional, Kousathanas, Athanasios, additional, Lahnstein, Lea, additional, Leigh, Sarah E.A., additional, Leong, Ivonne U.S., additional, Lopez, Javier F., additional, Maleady-Crowe, Fiona, additional, McEntagart, Meriel, additional, Minneci, Federico, additional, Moutsianas, Loukas, additional, Mueller, Michael, additional, Murugaesu, Nirupa, additional, Need, Anna C., additional, O’Donovan, Peter, additional, Odhams, Chris A., additional, Patch, Christine, additional, Pereira, Mariana Buongermino, additional, Perez-Gil, Daniel, additional, Pullinger, John, additional, Rahim, Tahrima, additional, Rendon, Augusto, additional, Rogers, Tim, additional, Savage, Kevin, additional, Sawant, Kushmita, additional, Scott, Richard H., additional, Siddiq, Afshan, additional, Sieghart, Alexander, additional, Smith, Samuel C., additional, Sosinsky, Alona, additional, Stuckey, Alexander, additional, Tanguy, Mélanie, additional, Taylor Tavares, Ana Lisa, additional, Thomas, Ellen R.A., additional, Thompson, Simon R., additional, Tucci, Arianna, additional, Welland, Matthew J., additional, Williams, Eleanor, additional, Witkowska, Katarzyna, additional, and Wood, Suzanne M., additional

Published
2023
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39. Heterozygous COL17A1variants are a frequent cause of amelogenesis imperfecta

Author

Hany, Ummey, Watson, Christopher M, Liu, Lu, Smith, Claire E L, Harfoush, Asmaa, Poulter, James A, Nikolopoulos, Georgios, Balmer, Richard, Brown, Catriona J, Patel, Anesha, Simmonds, Jenny, Charlton, Ruth, Acosta de Camargo, María Gabriela, Rodd, Helen D, Jafri, Hussain, Antanaviciute, Agne, Moffat, Michelle, Al-Jawad, Maisoon, Inglehearn, Chris F, and Mighell, Alan J

Abstract

BackgroundCollagen XVII is most typically associated with human disease when biallelic COL17A1variants (>230) cause junctional epidermolysis bullosa (JEB), a rare, genetically heterogeneous, mucocutaneous blistering disease with amelogenesis imperfecta (AI), a developmental enamel defect. Despite recognition that heterozygous carriers in JEB families can have AI, and that heterozygous COL17A1variants also cause dominant corneal epithelial recurrent erosion dystrophy (ERED), the importance of heterozygous COL17A1variants causing dominant non-syndromic AI is not widely recognised.MethodsProbands from an AI cohort were screened by single molecule molecular inversion probes or targeted hybridisation capture (both a custom panel and whole exome sequencing) for COL17A1variants. Patient phenotypes were assessed by clinical examination and analyses of affected teeth.ResultsNineteen unrelated probands with isolated AI (no co-segregating features) had 17 heterozygous, potentially pathogenic COL17A1variants, including missense, premature termination codons, frameshift and splice site variants in both the endo-domains and the ecto-domains of the protein. The AI phenotype was consistent with enamel of near normal thickness and variable focal hypoplasia with surface irregularities including pitting.ConclusionThese results indicate that COL17A1variants are a frequent cause of dominantly inherited non-syndromic AI. Comparison of variants implicated in AI and JEB identifies similarities in type and distribution, with five identified in both conditions, one of which may also cause ERED. Increased availability of genetic testing means that more individuals will receive reports of heterozygous COL17A1variants. We propose that patients with isolated AI or ERED, due to COL17A1variants, should be considered as potential carriers for JEB and counselled accordingly, reflecting the importance of multidisciplinary care.

Published
2024
Full Text
View/download PDF

40. Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis

Author

Panneman, Daan M., primary, Hitti-Malin, Rebekkah J., additional, Holtes, Lara K., additional, de Bruijn, Suzanne E., additional, Reurink, Janine, additional, Boonen, Erica G.M., additional, Khan, Muhammad Imran, additional, Ali, Manir, additional, Andréasson, Sten, additional, De Baere, Elfride, additional, Banfi, Sandro, additional, Bauwens, Miriam, additional, Ben-Yosef, Tamar, additional, Bocquet, Béatrice, additional, De Bruyne, Marieke, additional, de la Cerda, Berta, additional, Coppieters, Frauke, additional, Farinelli, Pietro, additional, Guignard, Thomas, additional, Inglehearn, Chris F., additional, Karali, Marianthi, additional, Kjellström, Ulrika, additional, Koenekoop, Robert, additional, de Koning, Bart, additional, Leroy, Bart P., additional, McKibbin, Martin, additional, Meunier, Isabelle, additional, Nikopoulos, Konstantinos, additional, Nishiguchi, Koji M., additional, Poulter, James A., additional, Rivolta, Carlo, additional, Rodríguez de la Rúa, Enrique, additional, Saunders, Patrick, additional, Simonelli, Francesca, additional, Tatour, Yasmin, additional, Testa, Francesco, additional, Thiadens, Alberta A.H.J., additional, Toomes, Carmel, additional, Tracewska, Anna M., additional, Viet Tran, Hoai, additional, Ushida, Hiroaki, additional, Vaclavik, Veronika, additional, Verhoeven, Virginie J.M., additional, van de Vorst, Maartje, additional, Gilissen, Christian, additional, Hoischen, Alexander, additional, Cremers, Frans P.M., additional, and Roosing, Susanne, additional

Published
2022
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41. Reply

Author

Inglehearn, Chris F., primary, Yahya, Samar, additional, Smith, Claire E.L., additional, Poulter, James A., additional, Ali, Manir, additional, Toomes, Carmel, additional, Ellingford, Jamie, additional, Black, Graeme C., additional, Arno, Gavin, additional, and Webster, Andrew R., additional

Published
2022
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44. ZNF408 is mutated in familial exudative vitreoretinopathy and is crucial for the development of zebrafish retinal vasculature

Author

Collin, Rob W. J., Nikopoulos, Konstantinos, Dona, Margo, Gilissen, Christian, Hoischen, Alexander, Boonstra, F. Nienke, Poulter, James A., Kondo, Hiroyuki, Berger, Wolfgang, Toomes, Carmel, Tahira, Tomoko, Mohn, Lucas R., Blokland, Ellen A., Hetterschijt, Lisette, Ali, Manir, Groothuismink, Johanne M., Duijkers, Lonneke, Inglehearn, Chris F., Sollfrank, Lea, Strom, Tim M., Uchio, Eiichi, van Nouhuys, C. Erik, Kremer, Hannie, Veltman, Joris A., van Wijk, Erwin, and Cremers, Frans P. M.

Published
2013

49. Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100 000 genomes project

Author

Best, Sunayna, primary, Lord, Jenny, additional, Roche, Matthew, additional, Watson, Christopher, additional, Poulter, James, additional, Szymanska, Katarzyna, additional, Ellingford, Jamie, additional, Carmichael, Jenny, additional, Brittain, Helen, additional, Toomes, Carmel, additional, Inglehearn, Chris, additional, Johnson, Colin, additional, and Wheway, Gabrielle, additional

Published
2022
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