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1. Rare disease gene association discovery in the 100,000 Genomes Project

Author

Cipriani, Valentina, Vestito, Letizia, Magavern, Emma F., Jacobsen, Julius O. B., Arno, Gavin, Behr, Elijah R., Benson, Katherine A., Bertoli, Marta, Bockenhauer, Detlef, Bowl, Michael R., Burley, Kate, Chan, Li F., Chinnery, Patrick, Conlon, Peter J., Costa, Marcos A., Davidson, Alice E., Dawson, Sally J., Elhassan, Elhussein A. E., Flanagan, Sarah E., Futema, Marta, Gale, Daniel P., García-Ruiz, Sonia, Corcia, Cecilia Gonzalez, Griffin, Helen R., Hambleton, Sophie, Hicks, Amy R., Houlden, Henry, Houlston, Richard S., Howles, Sarah A., Kleta, Robert, Lekkerkerker, Iris, Lin, Siying, Liskova, Petra, Mitchison, Hannah H., Morsy, Heba, Mumford, Andrew D., Newman, William G., Neatu, Ruxandra, O’Toole, Edel A., Ong, Albert C. M., Pagnamenta, Alistair T., Rahman, Shamima, Rajan, Neil, Robinson, Peter N., Ryten, Mina, Sadeghi-Alavijeh, Omid, Sayer, John A., Shovlin, Claire L., Taylor, Jenny C., Teltsh, Omri, Tomlinson, Ian, Tucci, Arianna, Turnbull, Clare, van Eerde, Albertien M., Ware, James S., Watts, Laura M., Webster, Andrew R., Westbury, Sarah K., Zheng, Sean L., Caulfield, Mark, and Smedley, Damian

Published
2025
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2. Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2

Author

Gahbauer, Stefan, Correy, Galen J, Schuller, Marion, Ferla, Matteo P, Doruk, Yagmur Umay, Rachman, Moira, Wu, Taiasean, Diolaiti, Morgan, Wang, Siyi, Neitz, R Jeffrey, Fearon, Daren, Radchenko, Dmytro S, Moroz, Yurii S, Irwin, John J, Renslo, Adam R, Taylor, Jenny C, Gestwicki, Jason E, von Delft, Frank, Ashworth, Alan, Ahel, Ivan, Shoichet, Brian K, and Fraser, James S

Subjects
Theory Of Computation, Biochemistry and Cell Biology, Biological Sciences, Medicinal and Biomolecular Chemistry, Chemical Sciences, Built Environment and Design, Information and Computing Sciences, Design, Emerging Infectious Diseases, Bioengineering, Infectious Diseases, Coronaviruses, 5.1 Pharmaceuticals, Generic health relevance, Humans, SARS-CoV-2, COVID-19, Crystallography, Pandemics, Ligands, Molecular Docking Simulation, Protease Inhibitors, Antiviral Agents, coronavirus, macrodomain, virtual screening, fragment-based drug discovery
Abstract

The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small-molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic, there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high-resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 153 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated conformational changes within the active site, and key inhibitor motifs that will template future drug development against Mac1.

Published
2023

3. Familial severe skeletal Class II malocclusion with gingival hyperplasia caused by a complex structural rearrangement at the KCNJ2-KCNJ16 locus

Author

Maroofian, Reza, Pagnamenta, Alistair T., Navabazam, Alireza, Schwessinger, Ron, Roberts, Hannah E., Lopopolo, Maria, Dehghani, Mohammadreza, Vahidi Mehrjardi, Mohammad Yahya, Haerian, Alireza, Soltanianzadeh, Mojtaba, Noori Kooshki, Mohammad Hadi, Knight, Samantha J.L., Miller, Kerry A., McGowan, Simon J., Chatron, Nicolas, Timberlake, Andrew T., Melo, Uirá Souto, Mundlos, Stefan, Buck, David, Twigg, Stephen R.F., Taylor, Jenny C., Wilkie, Andrew O.M., and Calpena, Eduardo

Published
2024
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4. The impact of inversions across 33,924 families with rare disease from a national genome sequencing project

Author

Pagnamenta, Alistair T., Yu, Jing, Walker, Susan, Noble, Alexandra J., Lord, Jenny, Dutta, Prasun, Hashim, Mona, Camps, Carme, Green, Hannah, Devaiah, Smrithi, Nashef, Lina, Parr, Jason, Fratter, Carl, Ibnouf Hussein, Rana, Lindsay, Sarah J., Lalloo, Fiona, Banos-Pinero, Benito, Evans, David, Mallin, Lucy, Waite, Adrian, Evans, Julie, Newman, Andrew, Allen, Zoe, Perez-Becerril, Cristina, Ryan, Gavin, Hart, Rachel, Taylor, John, Bedenham, Tina, Clement, Emma, Blair, Ed, Hay, Eleanor, Forzano, Francesca, Higgs, Jenny, Canham, Natalie, Majumdar, Anirban, McEntagart, Meriel, Lahiri, Nayana, Stewart, Helen, Smithson, Sarah, Calpena, Eduardo, Jackson, Adam, Banka, Siddharth, Titheradge, Hannah, McGowan, Ruth, Rankin, Julia, Shaw-Smith, Charles, Evans, D. Gareth, Burghel, George J., Smith, Miriam J., Anderson, Emily, Madhu, Rajesh, Firth, Helen, Ellard, Sian, Brennan, Paul, Anderson, Claire, Taupin, Doug, Rogers, Mark T., Cook, Jackie A., Durkie, Miranda, East, James E., Fowler, Darren, Wilson, Louise, Igbokwe, Rebecca, Gardham, Alice, Tomlinson, Ian, Baralle, Diana, Uhlig, Holm H., and Taylor, Jenny C.

Published
2024
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5. Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Author

Pagnamenta, Alistair T., Camps, Carme, Giacopuzzi, Edoardo, Taylor, John M., Hashim, Mona, Calpena, Eduardo, Kaisaki, Pamela J., Hashimoto, Akiko, Yu, Jing, Sanders, Edward, Schwessinger, Ron, Hughes, Jim R., Lunter, Gerton, Dreau, Helene, Ferla, Matteo, Lange, Lukas, Kesim, Yesim, Ragoussis, Vassilis, Vavoulis, Dimitrios V., Allroggen, Holger, Ansorge, Olaf, Babbs, Christian, Banka, Siddharth, Baños-Piñero, Benito, Beeson, David, Ben-Ami, Tal, Bennett, David L., Bento, Celeste, Blair, Edward, Brasch-Andersen, Charlotte, Bull, Katherine R., Cario, Holger, Cilliers, Deirdre, Conti, Valerio, Davies, E. Graham, Dhalla, Fatima, Dacal, Beatriz Diez, Dong, Yin, Dunford, James E., Guerrini, Renzo, Harris, Adrian L., Hartley, Jane, Hollander, Georg, Javaid, Kassim, Kane, Maureen, Kelly, Deirdre, Kelly, Dominic, Knight, Samantha J. L., Kreins, Alexandra Y., Kvikstad, Erika M., Langman, Craig B., Lester, Tracy, Lines, Kate E., Lord, Simon R., Lu, Xin, Mansour, Sahar, Manzur, Adnan, Maroofian, Reza, Marsden, Brian, Mason, Joanne, McGowan, Simon J., Mei, Davide, Mlcochova, Hana, Murakami, Yoshiko, Németh, Andrea H., Okoli, Steven, Ormondroyd, Elizabeth, Ousager, Lilian Bomme, Palace, Jacqueline, Patel, Smita Y., Pentony, Melissa M., Pugh, Chris, Rad, Aboulfazl, Ramesh, Archana, Riva, Simone G., Roberts, Irene, Roy, Noémi, Salminen, Outi, Schilling, Kyleen D., Scott, Caroline, Sen, Arjune, Smith, Conrad, Stevenson, Mark, Thakker, Rajesh V., Twigg, Stephen R. F., Uhlig, Holm H., van Wijk, Richard, Vona, Barbara, Wall, Steven, Wang, Jing, Watkins, Hugh, Zak, Jaroslav, Schuh, Anna H., Kini, Usha, Wilkie, Andrew O. M., Popitsch, Niko, and Taylor, Jenny C.

Published
2023
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6. Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype–phenotype correlation study

Author

Loong, Lucy, Tardivo, Agostina, Knaus, Alexej, Hashim, Mona, Pagnamenta, Alistair T., Alt, Kerstin, Böhrer-Rabel, Helena, Caro-Llopis, Alfonso, Cole, Trevor, Distelmaier, Felix, Edery, Patrick, Ferreira, Carlos R., Jezela-Stanek, Aleksandra, Kerr, Bronwyn, Kluger, Gerhard, Krawitz, Peter M., Kuhn, Marius, Lemke, Johannes R., Lesca, Gaetan, Lynch, Sally Ann, Martinez, Francisco, Maxton, Caroline, Mierzewska, Hanna, Monfort, Sandra, Nicolai, Joost, Orellana, Carmen, Pal, Deb K., Płoski, Rafał, Quarrell, Oliver W., Rosello, Monica, Rydzanicz, Małgorzata, Sabir, Ataf, Śmigiel, Robert, Stegmann, Alexander P.A., Stewart, Helen, Stumpel, Constance, Szczepanik, Elżbieta, Tzschach, Andreas, Wolfe, Lynne, Taylor, Jenny C., Murakami, Yoshiko, Kinoshita, Taroh, Bayat, Allan, and Kini, Usha

Published
2023
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8. Fragmenstein: predicting protein–ligand structures of compounds derived from known crystallographic fragment hits using a strict conserved-binding–based methodology.

Author

Ferla, Matteo P., Sánchez-García, Rubén, Skyner, Rachael E., Gahbauer, Stefan, Taylor, Jenny C., von Delft, Frank, Marsden, Brian D., and Deane, Charlotte M.

Subjects
LIFE sciences, SINGLE parents, DRUG design, CYTOLOGY, MERGERS & acquisitions
Abstract

Current strategies centred on either merging or linking initial hits from fragment-based drug design (FBDD) crystallographic screens generally do not fully leaverage 3D structural information. We show that an algorithmic approach (Fragmenstein) that 'stitches' the ligand atoms from this structural information together can provide more accurate and reliable predictions for protein–ligand complex conformation than general methods such as pharmacophore-constrained docking. This approach works under the assumption of conserved binding: when a larger molecule is designed containing the initial fragment hit, the common substructure between the two will adopt the same binding mode. Fragmenstein either takes the atomic coordinates of ligands from a experimental fragment screen and combines the atoms together to produce a novel merged virtual compound, or uses them to predict the bound complex for a provided molecule. The molecule is then energy minimised under strong constraints to obtain a structurally plausible conformer. The code is available at https://github.com/oxpig/Fragmenstein. Scientific contribution This work shows the importance of using the coordinates of known binders when predicting the conformation of derivative molecules through a retrospective analysis of the COVID Moonshot data. This method has had a prior real-world application in hit-to-lead screening, yielding a sub-micromolar merger from parent hits in a single round. It is therefore likely to further benefit future drug design campaigns and be integrated in future pipelines. [ABSTRACT FROM AUTHOR]

Published
2025
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9. Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations

Author

Tripathy, Ratna, Leca, Ines, van Dijk, Tessa, Weiss, Janneke, van Bon, Bregje W, Sergaki, Maria Christina, Gstrein, Thomas, Breuss, Martin, Tian, Guoling, Bahi-Buisson, Nadia, Paciorkowski, Alexander R, Pagnamenta, Alistair T, Wenninger-Weinzierl, Andrea, Martinez-Reza, Maria Fernanda, Landler, Lukas, Lise, Stefano, Taylor, Jenny C, Terrone, Gaetano, Vitiello, Giuseppina, Del Giudice, Ennio, Brunetti-Pierri, Nicola, D’Amico, Alessandra, Reymond, Alexandre, Voisin, Norine, Bernstein, Jonathan A, Farrelly, Ellyn, Kini, Usha, Leonard, Thomas A, Valence, Stéphanie, Burglen, Lydie, Armstrong, Linlea, Hiatt, Susan M, Cooper, Gregory M, Aldinger, Kimberly A, Dobyns, William B, Mirzaa, Ghayda, Pierson, Tyler Mark, Baas, Frank, Chelly, Jamel, Cowan, Nicholas J, and Keays, David Anthony

Subjects
Biomedical and Clinical Sciences, Neurosciences, Rare Diseases, Pediatric, Genetics, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Congenital Structural Anomalies, 2.1 Biological and endogenous factors, Aetiology, Neurological, Agenesis of Corpus Callosum, Animals, Animals, Newborn, Apoptosis, Brain, Cells, Cultured, Cerebellum, Child, Developmental Disabilities, Disease Models, Animal, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental, Humans, Male, Malformations of Cortical Development, Mice, Mice, Inbred C57BL, Mice, Knockout, Microtubule-Associated Proteins, Mutation, Nerve Tissue Proteins, Nervous System Malformations, PAX6 Transcription Factor, MAST1, cerebellar hypoplasia, corpus callosum, microdeletion, microtubules, Psychology, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.

Published
2018

10. Recommendations for clinical interpretation of variants found in non-coding regions of the genome

Author

Ellingford, Jamie M., Ahn, Joo Wook, Bagnall, Richard D., Baralle, Diana, Barton, Stephanie, Campbell, Chris, Downes, Kate, Ellard, Sian, Duff-Farrier, Celia, FitzPatrick, David R., Greally, John M., Ingles, Jodie, Krishnan, Neesha, Lord, Jenny, Martin, Hilary C., Newman, William G., O’Donnell-Luria, Anne, Ramsden, Simon C., Rehm, Heidi L., Richardson, Ebony, Singer-Berk, Moriel, Taylor, Jenny C., Williams, Maggie, Wood, Jordan C., Wright, Caroline F., Harrison, Steven M., and Whiffin, Nicola

Published
2022
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11. Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms

Author

Wright, Caroline F., Quaife, Nicholas M., Ramos-Hernández, Laura, Danecek, Petr, Ferla, Matteo P., Samocha, Kaitlin E., Kaplanis, Joanna, Gardner, Eugene J., Eberhardt, Ruth Y., Chao, Katherine R., Karczewski, Konrad J., Morales, Joannella, Gallone, Giuseppe, Balasubramanian, Meena, Banka, Siddharth, Gompertz, Lianne, Kerr, Bronwyn, Kirby, Amelia, Lynch, Sally A., Morton, Jenny E.V., Pinz, Hailey, Sansbury, Francis H., Stewart, Helen, Zuccarelli, Britton D., Cook, Stuart A., Taylor, Jenny C., Juusola, Jane, Retterer, Kyle, Firth, Helen V., Hurles, Matthew E., Lara-Pezzi, Enrique, Barton, Paul J.R., and Whiffin, Nicola

Published
2021
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13. SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

Author

Lin, Yuh-Charn, Niceta, Marcello, Muto, Valentina, Vona, Barbara, Pagnamenta, Alistair T., Maroofian, Reza, Beetz, Christian, van Duyvenvoorde, Hermine, Dentici, Maria Lisa, Lauffer, Peter, Vallian, Sadeq, Ciolfi, Andrea, Pizzi, Simone, Bauer, Peter, Grüning, Nana-Maria, Bellacchio, Emanuele, Del Fattore, Andrea, Petrini, Stefania, Shaheen, Ranad, Tiosano, Dov, Halloun, Rana, Pode-Shakked, Ben, Albayrak, Hatice Mutlu, Işık, Emregül, Wit, Jan M., Dittrich, Marcus, Freire, Bruna L., Bertola, Debora R., Jorge, Alexander A.L., Barel, Ortal, Sabir, Ataf H., Al Tenaiji, Amal M.J., Taji, Sulaima M., Al-Sannaa, Nouriya, Al-Abdulwahed, Hind, Digilio, Maria Cristina, Irving, Melita, Anikster, Yair, Bhavani, Gandham S.L., Girisha, Katta M., Haaf, Thomas, Taylor, Jenny C., Dallapiccola, Bruno, Alkuraya, Fowzan S., Yang, Ruey-Bing, and Tartaglia, Marco

Published
2021
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14. A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome

Author

Twigg, Stephen RF, Hufnagel, Robert B, Miller, Kerry A, Zhou, Yan, McGowan, Simon J, Taylor, John, Craft, Jude, Taylor, Jenny C, Santoro, Stephanie L, Huang, Taosheng, Hopkin, Robert J, Brady, Angela F, Clayton-Smith, Jill, Clericuzio, Carol L, Grange, Dorothy K, Groesser, Leopold, Hafner, Christian, Horn, Denise, Temple, I Karen, Dobyns, William B, Curry, Cynthia J, Jones, Marilyn C, and Wilkie, Andrew OM

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Brain Disorders, Rare Diseases, Brain Cancer, Clinical Research, Neurosciences, Cancer, Pediatric, Genetics, Child, Preschool, Craniofacial Abnormalities, Female, Humans, Infant, Infant, Newborn, Intestines, Male, Mutation, Signal Transduction, Skin Abnormalities, Smoothened Receptor, Syndactyly, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism.

Published
2016

17. De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia

Author

Haijes, Hanneke A., Koster, Maria J.E., Rehmann, Holger, Li, Dong, Hakonarson, Hakon, Cappuccio, Gerarda, Hancarova, Miroslava, Lehalle, Daphne, Reardon, Willie, Schaefer, G. Bradley, Lehman, Anna, van de Laar, Ingrid M.B.H., Tesselaar, Coranne D., Turner, Clesson, Goldenberg, Alice, Patrier, Sophie, Thevenon, Julien, Pinelli, Michele, Brunetti-Pierri, Nicola, Prchalová, Darina, Havlovicová, Markéta, Vlckova, Markéta, Sedláček, Zdeněk, Lopez, Elena, Ragoussis, Vassilis, Pagnamenta, Alistair T., Kini, Usha, Vos, Harmjan R., van Es, Robert M., van Schaik, Richard F.M.A., van Essen, Ton A.J., Kibaek, Maria, Taylor, Jenny C., Sullivan, Jennifer, Shashi, Vandana, Petrovski, Slave, Fagerberg, Christina, Martin, Donna M., van Gassen, Koen L.I., Pfundt, Rolph, Falk, Marni J., McCormick, Elizabeth M., Timmers, H.T. Marc, and van Hasselt, Peter M.

Published
2019
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18. The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature

Author

Piard, Juliette, Hawkes, Lara, Milh, Mathieu, Villard, Laurent, Borgatti, Renato, Romaniello, Romina, Fradin, Melanie, Capri, Yline, Héron, Delphine, Nougues, Marie-Christine, Nava, Caroline, Arsene, Oana Tarta, Shears, Debbie, Taylor, John, Pagnamenta, Alistair, Taylor, Jenny C, Sogawa, Yoshimi, Johnson, Diana, Firth, Helen, Vasudevan, Pradeep, Jones, Gabriela, Nguyen-Morel, Marie-Ange, Busa, Tiffany, Roubertie, Agathe, van den Born, Myrthe, Brischoux-Boucher, Elise, Koenig, Michel, Mignot, Cyril, Kini, Usha, and Philippe, Christophe

Published
2019
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20. Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening

Author

Baxley, Ryan M., Leung, Wendy, Schmit, Megan M., Matson, Jacob Peter, Yin, Lulu, Oram, Marissa K., Wang, Liangjun, Taylor, John, Hedberg, Jack, Rogers, Colette B., Harvey, Adam J., Basu, Debashree, Taylor, Jenny C., Pagnamenta, Alistair T., Dreau, Helene, Craft, Jude, Ormondroyd, Elizabeth, Watkins, Hugh, Hendrickson, Eric A., Mace, Emily M., Orange, Jordan S., Aihara, Hideki, Stewart, Grant S., Blair, Edward, Cook, Jeanette Gowen, and Bielinsky, Anja-Katrin

Published
2021
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23. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants

Author

Johnston, Jennifer J., van der Smagt, Jasper J., Rosenfeld, Jill A., Pagnamenta, Alistair T., Alswaid, Abdulrahman, Baker, Eva H., Blair, Edward, Borck, Guntram, Brinkmann, Julia, Craigen, William, Dung, Vu Chi, Emrick, Lisa, Everman, David B., van Gassen, Koen L., Gulsuner, Suleyman, Harr, Margaret H., Jain, Mahim, Kuechler, Alma, Leppig, Kathleen A., McDonald-McGinn, Donna M., Can, Ngoc Thi Bich, Peleg, Amir, Roeder, Elizabeth R., Rogers, R.Curtis, Sagi-Dain, Lena, Sapp, Julie C., Schäffer, Alejandro A., Schanze, Denny, Stewart, Helen, Taylor, Jenny C., Verbeek, Nienke E., Walkiewicz, Magdalena A., Zackai, Elaine H., Zweier, Christiane, Zenker, Martin, Lee, Brendan, and Biesecker, Leslie G.

Published
2018
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24. Clinical whole-genome sequencing from routine formalin-fixed, paraffin-embedded specimens: pilot study for the 100,000 Genomes Project

Author

Robbe, Pauline, Popitsch, Niko, Knight, Samantha J.L., Antoniou, Pavlos, Becq, Jennifer, He, Miao, Kanapin, Alexander, Samsonova, Anastasia, Vavoulis, Dimitrios V., Ross, Mark T., Kingsbury, Zoya, Cabes, Maite, Ramos, Sara D.C., Page, Suzanne, Dreau, Helene, Ridout, Kate, Jones, Louise J., Tuff-Lacey, Alice, Henderson, Shirley, Mason, Joanne, Buffa, Francesca M., Verrill, Clare, Maldonado-Perez, David, Roxanis, Ioannis, Collantes, Elena, Browning, Lisa, Dhar, Sunanda, Damato, Stephen, Davies, Susan, Caulfield, Mark, Bentley, David R., Taylor, Jenny C., Turnbull, Clare, and Schuh, Anna

Published
2018
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25. Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease

Author

Lenglet, Marion, Robriquet, Florence, Schwarz, Klaus, Camps, Carme, Couturier, Anne, Hoogewijs, David, Buffet, Alexandre, Knight, Samantha J.L., Gad, Sophie, Couvé, Sophie, Chesnel, Franck, Pacault, Mathilde, Lindenbaum, Pierre, Job, Sylvie, Dumont, Solenne, Besnard, Thomas, Cornec, Marine, Dreau, Helene, Pentony, Melissa, Kvikstad, Erika, Deveaux, Sophie, Burnichon, Nelly, Ferlicot, Sophie, Vilaine, Mathias, Mazzella, Jean-Michaël, Airaud, Fabrice, Garrec, Céline, Heidet, Laurence, Irtan, Sabine, Mantadakis, Elpis, Bouchireb, Karim, Debatin, Klaus-Michael, Redon, Richard, Bezieau, Stéphane, Bressac-de Paillerets, Brigitte, Teh, Bin Tean, Girodon, François, Randi, Maria-Luigia, Putti, Maria Caterina, Bours, Vincent, Van Wijk, Richard, Göthert, Joachim R., Kattamis, Antonis, Janin, Nicolas, Bento, Celeste, Taylor, Jenny C., Arlot-Bonnemains, Yannick, Richard, Stéphane, Gimenez-Roqueplo, Anne-Paule, Cario, Holger, and Gardie, Betty

Published
2018
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30. Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders

Author

Maroofian, Reza, primary, Kaiyrzhanov, Rauan, additional, Cali, Elisa, additional, Zamani, Mina, additional, Zaki, Maha S, additional, Ferla, Matteo, additional, Tortora, Domenico, additional, Sadeghian, Saeid, additional, Saadi, Saadia Maryam, additional, Abdullah, Uzma, additional, Karimiani, Ehsan Ghayoor, additional, Efthymiou, Stephanie, additional, Yeşil, Gözde, additional, Alavi, Shahryar, additional, Al Shamsi, Aisha M, additional, Tajsharghi, Homa, additional, Abdel-Hamid, Mohamed S, additional, Saadi, Nebal Waill, additional, Al Mutairi, Fuad, additional, Alabdi, Lama, additional, Beetz, Christian, additional, Ali, Zafar, additional, Toosi, Mehran Beiraghi, additional, Rudnik-Schöneborn, Sabine, additional, Babaei, Meisam, additional, Isohanni, Pirjo, additional, Muhammad, Jameel, additional, Khan, Sheraz, additional, Al Shalan, Maha, additional, Hickey, Scott E, additional, Marom, Daphna, additional, Elhanan, Emil, additional, Kurian, Manju A, additional, Marafi, Dana, additional, Saberi, Alihossein, additional, Hamid, Mohammad, additional, Spaull, Robert, additional, Meng, Linyan, additional, Lalani, Seema, additional, Maqbool, Shazia, additional, Rahman, Fatima, additional, Seeger, Jürgen, additional, Palculict, Timothy Blake, additional, Lau, Tracy, additional, Murphy, David, additional, Mencacci, Niccolo Emanuele, additional, Steindl, Katharina, additional, Begemann, Anais, additional, Rauch, Anita, additional, Akbas, Sinan, additional, Aslanger, Ayça Dilruba, additional, Salpietro, Vincenzo, additional, Yousaf, Hammad, additional, Ben-Shachar, Shay, additional, Ejeskär, Katarina, additional, Al Aqeel, Aida I, additional, High, Frances A, additional, Armstrong-Javors, Amy E, additional, Zahraei, Seyed Mohammadsaleh, additional, Seifi, Tahereh, additional, Zeighami, Jawaher, additional, Shariati, Gholamreza, additional, Sedaghat, Alireza, additional, Asl, Samaneh Noroozi, additional, Shahrooei, Mohmmad, additional, Zifarelli, Giovanni, additional, Burglen, Lydie, additional, Ravelli, Claudia, additional, Zschocke, Johannes, additional, Schatz, Ulrich A, additional, Ghavideldarestani, Maryam, additional, Kamel, Walaa A, additional, Van Esch, Hilde, additional, Hackenberg, Annette, additional, Taylor, Jenny C, additional, Al-Gazali, Lihadh, additional, Bauer, Peter, additional, Gleeson, Joseph J, additional, Alkuraya, Fowzan Sami, additional, Lupski, James R, additional, Galehdari, Hamid, additional, Azizimalamiri, Reza, additional, Chung, Wendy K, additional, Baig, Shahid Mahmood, additional, Houlden, Henry, additional, and Severino, Mariasavina, additional

Published
2023
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31. Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome

Author

Hannah, Michael G., Bugiardini, Enrico, Bertini, Enrico, Kriouile, Yamna, El-Khorassani, Mohamed, Aguennouz, Mhammed, Groppa, Stanislav, Karashova, Blagovesta M., Goraya, Jatinder S., Sultan, Tipu, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Banu, Selina, Veggiotti, Pierangelo, Verrotti, Alberto, Lanari, Marcello, Savasta, Salvatore, Macaya, Alfons, Garavaglia, Barbara, Borgione, Eugenia, Papacostas, Savvas, Vikelis, Michail, Chelban, Viorica, Kaiyrzhanov, Rauan, Cortese, Andrea, Sullivan, Roisin, Papanicolaou, Eleni Z., Dardiotis, Efthymios, Maqbool, Shazia, Ibrahim, Shahnaz, Kirmani, Salman, Rana, Nuzhat N., Atawneh, Osama, Lim, Shen-Yang, Zuccotti, Gian V., Marseglia, Gian L., Esposito, Susanna, Shaikh, Farooq, Cogo, Paola, Corsello, Giovanni, Mangano, Salvatore, Nardello, Rosaria, Mangano, Donato, Scardamaglia, Annarita, Koutsis, George, Scuderi, Carmela, Ferrara, Pietro, Morello, Giovanna, Zollo, Massimo, Berni-Canani, Roberto, Terracciano, Luigi M., Sisto, Antonio, Di Fabio, Sandra, Strano, Federica, Scorrano, Giovanna, Di Bella, Saverio, Di Francesco, Ludovica, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Xiromerisiou, Georgia, Spanaki, Cleanthe, Fiorillo, Chiara, Iacomino, Michele, Gaudio, Eugenio, Munell, Francina, Gagliano, Antonella, Jan, Farida, Chimenz, Roberto, Gitto, Eloisa, Iughetti, Lorenzo, Di Rosa, Gabriella, Maghnie, Mohamad, Pettoello-Mantovani, Massimo, Gupta, Neerja, Kabra, Madhulika, Benrhouma, Hanene, Tazir, Meriem, Bottone, Gabriella, Farello, Giovanni, Delvecchio, Maurizio, Di-Donato, Giulio, Obeid, Makram, Bakhtadze, Sophia, Saadi, Nebal W., Miraglia-Del-Giudice, Michele, Maccarone, Rita, Zaki, Maha S., Triki, Chahnez C., Kara, Majdi, Karimiani, Ehsan G., Salih, Ahmed M., Ramenghi, Luca A., Seri, Marco, Di-Falco, Giovanna, Mandarà, Luana, Barrano, Giuseppe, Elisa, Maurizio, Cherubini, Enrico, Operto, Francesca F., Valenzise, Mariella, Cattaneo, Antonino, Zazzeroni, Francesca, Alesse, Edoardo, Matricardi, Sara, Zafar, Faisal, Ullah, Ehsan, Afzal, Erum, Rahman, Fatima, Ahmed, Muhammad M., Parisi, Pasquale, Spalice, Alberto, De Filippo, Maria, Licari, Amelia, Trebbi, Edoardo, Romano, Ferdinando, Heimer, Gali, Al-Khawaja, Issam, Al-Mutairi, Fuad, Alkuraya, Fowzan S., Rizig, Mie, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Salpietro, Vincenzo, Maroofian, Reza, Wangen, Jamie, Ciolfi, Andrea, Barresi, Sabina, Efthymiou, Stephanie, Lamaze, Angelique, Aughey, Gabriel N., Al Mutairi, Fuad, Rad, Aboulfazl, Rocca, Clarissa, Calì, Elisa, Accogli, Andrea, Zara, Federico, Striano, Pasquale, Mojarrad, Majid, Tariq, Huma, Giacopuzzi, Edoardo, Taylor, Jenny C., Oprea, Gabriela, Skrahina, Volha, Rehman, Khalil Ur, Abd Elmaksoud, Marwa, Bassiony, Mahmoud, El Said, Huda G., Abdel-Hamid, Mohamed S., Al Shalan, Maha, Seo, Gohun, Kim, Sohyun, Lee, Hane, Khang, Rin, Issa, Mahmoud Y., Elbendary, Hasnaa M., Rafat, Karima, Marinakis, Nikolaos M., Traeger-Synodinos, Joanne, Ververi, Athina, Sourmpi, Mara, Eslahi, Atieh, Khadivi Zand, Farhad, Beiraghi Toosi, Mehran, Babaei, Meisam, Jackson, Adam, Bertoli-Avella, Aida, Pagnamenta, Alistair T., Niceta, Marcello, Battini, Roberta, Corsello, Antonio, Leoni, Chiara, Chiarelli, Francesco, Dallapiccola, Bruno, Faqeih, Eissa Ali, Tallur, Krishnaraya K., Alfadhel, Majid, Alobeid, Eman, Maddirevula, Sateesh, Mankad, Kshitij, Banka, Siddharth, Ghayoor-Karimiani, Ehsan, Tartaglia, Marco, Chung, Wendy K., Green, Rachel, Jepson, James E.C., and Houlden, Henry

Published
2024
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32. De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation

Author

Haas, Matilda A., Ngo, Linh, Li, Shan Shan, Schleich, Sibylle, Qu, Zhengdong, Vanyai, Hannah K., Cullen, Hayley D., Cardona-Alberich, Aida, Gladwyn-Ng, Ivan E., Pagnamenta, Alistair T., Taylor, Jenny C., Stewart, Helen, Kini, Usha, Duncan, Kent E., Teleman, Aurelio A., Keays, David A., and Heng, Julian I.-T.

Published
2016
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33. Implementation of a genomic medicine multi-disciplinary team approach for rare disease in the clinical setting: a prospective exome sequencing case series

Author

Taylor, John, Craft, Jude, Blair, Edward, Wordsworth, Sarah, Beeson, David, Chandratre, Saleel, Cossins, Judith, Lester, Tracy, Németh, Andrea H., Ormondroyd, Elizabeth, Patel, Smita Y., Pagnamenta, Alistair T., Taylor, Jenny C., Thomson, Kate L., Watkins, Hugh, Wilkie, Andrew O. M., and Knight, Julian C.

Published
2019
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34. Sequencing of human genomes with nanopore technology

Author

Bowden, Rory, Davies, Robert W., Heger, Andreas, Pagnamenta, Alistair T., de Cesare, Mariateresa, Oikkonen, Laura E., Parkes, Duncan, Freeman, Colin, Dhalla, Fatima, Patel, Smita Y., Popitsch, Niko, Ip, Camilla L. C., Roberts, Hannah E., Salatino, Silvia, Lockstone, Helen, Lunter, Gerton, Taylor, Jenny C., Buck, David, Simpson, Michael A., and Donnelly, Peter

Published
2019
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35. Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data

Author

Genetica Groep Van Tintelen, Genetica Klinische Genetica, Cancer, Child Health, Cipriani, Valentina, Vestito, Letizia, Magavern, Emma F, Jacobsen, Julius Ob, Arno, Gavin, Behr, Elijah R, Benson, Katherine A, Bertoli, Marta, Bockenhauer, Detlef, Bowl, Michael R, Burley, Kate, Chan, Li F, Chinnery, Patrick, Conlon, Peter, Costa, Marcos, Davidson, Alice E, Dawson, Sally J, Elhassan, Elhussein, Flanagan, Sarah E, Futema, Marta, Gale, Daniel P, García-Ruiz, Sonia, Corcia, Cecilia Gonzalez, Griffin, Helen R, Hambleton, Sophie, Hicks, Amy R, Houlden, Henry, Houlston, Richard S, Howles, Sarah A, Kleta, Robert, Lekkerkerker, Iris, Lin, Siying, Liskova, Petra, Mitchison, Hannah, Morsy, Heba, Mumford, Andrew D, Newman, William G, Neatu, Ruxandra, O'Toole, Edel A, Ong, Albert Cm, Pagnamenta, Alistair T, Rahman, Shamima, Rajan, Neil, Robinson, Peter N, Ryten, Mina, Sadeghi-Alavijeh, Omid, Sayer, John A, Shovlin, Claire L, Taylor, Jenny C, Teltsh, Omri, Tomlinson, Ian, Tucci, Arianna, Turnbull, Clare, van Eerde, Albertien M, Ware, James S, Watts, Laura M, Webster, Andrew R, Westbury, Sarah K, Zheng, Sean L, Caulfield, Mark, Smedley, Damian, Genetica Groep Van Tintelen, Genetica Klinische Genetica, Cancer, Child Health, Cipriani, Valentina, Vestito, Letizia, Magavern, Emma F, Jacobsen, Julius Ob, Arno, Gavin, Behr, Elijah R, Benson, Katherine A, Bertoli, Marta, Bockenhauer, Detlef, Bowl, Michael R, Burley, Kate, Chan, Li F, Chinnery, Patrick, Conlon, Peter, Costa, Marcos, Davidson, Alice E, Dawson, Sally J, Elhassan, Elhussein, Flanagan, Sarah E, Futema, Marta, Gale, Daniel P, García-Ruiz, Sonia, Corcia, Cecilia Gonzalez, Griffin, Helen R, Hambleton, Sophie, Hicks, Amy R, Houlden, Henry, Houlston, Richard S, Howles, Sarah A, Kleta, Robert, Lekkerkerker, Iris, Lin, Siying, Liskova, Petra, Mitchison, Hannah, Morsy, Heba, Mumford, Andrew D, Newman, William G, Neatu, Ruxandra, O'Toole, Edel A, Ong, Albert Cm, Pagnamenta, Alistair T, Rahman, Shamima, Rajan, Neil, Robinson, Peter N, Ryten, Mina, Sadeghi-Alavijeh, Omid, Sayer, John A, Shovlin, Claire L, Taylor, Jenny C, Teltsh, Omri, Tomlinson, Ian, Tucci, Arianna, Turnbull, Clare, van Eerde, Albertien M, Ware, James S, Watts, Laura M, Webster, Andrew R, Westbury, Sarah K, Zheng, Sean L, Caulfield, Mark, and Smedley, Damian

Published
2023

36. A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency

Author

Pagnamenta, Alistair T., primary, Yu, Jing, additional, Willis, Tracey A., additional, Hashim, Mona, additional, Seaby, Eleanor G., additional, Walker, Susan, additional, Xian, Jiaqi, additional, Cheng, Emily W. Y., additional, Tavares, Ana Lisa Taylor, additional, Forzano, Francesca, additional, Cox, Helen, additional, Dabir, Tabib, additional, Brady, Angela F., additional, Ghali, Neeti, additional, Atanur, Santosh S., additional, Ennis, Sarah, additional, Baralle, Diana, additional, and Taylor, Jenny C., additional

Published
2023
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37. A palindrome-like structure on 16p13.3 is associated with the formation of complex structural variations and SRRM3 haploinsufficiency

Author

Pagnamenta, Alistair T., Jing, Yu, Willis, Tracey A., Hashim, Mona, Seaby, Eleanor Grace, Walker, Susan, Xian, Katrina, Cheng, Emily W.Y., Tavares, Ana Lisa Taylor, Forzano, Francesca, Cox, Helen, Brady, Angela F, Dabir, Tabib, Ghali, Neeti, Antanur, Santosh S., Ennis, Sarah, Baralle, Diana, and Taylor, Jenny C.

Abstract

SRRM2 encodes a splicing factor recently implicated in developmental disorders due to a statistical enrichment of de novo mutations. Using data from the 100,000 Genomes Project, four unrelated individuals with intellectual disability (ID) were identified, each harbouring de novo whole gene deletions of SRRM2. Deletions ranged between 248-482kb in size and all distal breakpoints clustered within a complex 144kb palindrome situated 75kb upstream of SRRM2. Strikingly, three of the deletions were complex, with inverted internal segments of 45-94kb. In one proband-mother duo, de novo status was inferred by haplotype analysis. Together with two additional patients who harboured smaller predicted protein truncating variants (p.Arg632* and p.Ala2223Leufs*13), we estimate the prevalence of this condition in cohorts of patients with unexplained ID to be ~1/1300. Phenotypic blending, present for two cases with additional pathogenic variants in CASR/PKD1 and SLC17A5, hampered phenotypic delineation of this recently described condition. Our data highlights the benefits of genome sequencing for resolving structural complexity and inferring de novo status. The genomic architecture of 16p13.3 may give rise to relatively high rates of complex rearrangements, adding to the list of loci associated with recurrent genomic disorders.

Published
2023

38. Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities

Author

Cali, Elisa, primary, Suri, Mohnish, additional, Scala, Marcello, additional, Ferla, Matteo P., additional, Alavi, Shahryar, additional, Faqeih, Eissa Ali, additional, Bijlsma, Emilia K., additional, Wigby, Kristen M., additional, Baralle, Diana, additional, Mehrjardi, Mohammad Y.V., additional, Schwab, Jennifer, additional, Platzer, Konrad, additional, Steindl, Katharina, additional, Hashem, Mais, additional, Jones, Marilyn, additional, Niyazov, Dmitriy M., additional, Jacober, Jennifer, additional, Littlejohn, Rebecca Okashah, additional, Weis, Denisa, additional, Zadeh, Neda, additional, Rodan, Lance, additional, Goldenberg, Alice, additional, Lecoquierre, François, additional, Dutra-Clarke, Marina, additional, Horvath, Gabriella, additional, Young, Dana, additional, Orenstein, Naama, additional, Bawazeer, Shahad, additional, Vulto-van Silfhout, Anneke T., additional, Herenger, Yvan, additional, Dehghani, Mohammadreza, additional, Seyedhassani, Seyed Mohammad, additional, Bahreini, Amir, additional, Nasab, Mahya E., additional, Ercan-Sencicek, A. Gulhan, additional, Firoozfar, Zahra, additional, Movahedinia, Mojtaba, additional, Efthymiou, Stephanie, additional, Striano, Pasquale, additional, Karimiani, Ehsan Ghayoor, additional, Salpietro, Vincenzo, additional, Taylor, Jenny C., additional, Redman, Melody, additional, Stegmann, Alexander P.A., additional, Laner, Andreas, additional, Abdel-Salam, Ghada, additional, Li, Megan, additional, Bengala, Mario, additional, Müller, Amelie Johanna, additional, Digilio, Maria C., additional, Rauch, Anita, additional, Gunel, Murat, additional, Titheradge, Hannah, additional, Schweitzer, Daniela N., additional, Kraus, Alison, additional, Valenzuela, Irene, additional, McLean, Scott D., additional, Phornphutkul, Chanika, additional, Salih, Mustafa, additional, Begtrup, Amber, additional, Schnur, Rhonda E., additional, Torti, Erin, additional, Haack, Tobias B., additional, Prada, Carlos E., additional, Alkuraya, Fowzan S., additional, Houlden, Henry, additional, and Maroofian, Reza, additional

Published
2023
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39. SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage

Author

Clifford, Ruth, Louis, Tania, Robbe, Pauline, Ackroyd, Sam, Burns, Adam, Timbs, Adele T., Wright Colopy, Glen, Dreau, Helene, Sigaux, Francois, Judde, Jean Gabriel, Rotger, Margalida, Telenti, Amalio, Lin, Yea-Lih, Pasero, Philippe, Maelfait, Jonathan, Titsias, Michalis, Cohen, Dena R., Henderson, Shirley J., Ross, Mark T., Bentley, David, Hillmen, Peter, Pettitt, Andrew, Rehwinkel, Jan, Knight, Samantha J.L., Taylor, Jenny C., Crow, Yanick J., Benkirane, Monsef, and Schuh, Anna

Published
2014
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40. Use of genome sequencing to hunt for cryptic second-hit variants: analysis of 31 cases recruited to the 100 000 Genomes Project.

Author

Moore, A. Rachel, Jing Yu, Yang Pei, Cheng, Emily W. Y., Taylor Tavares, Ana Lisa, Walker, Woolf T., Thomas, N. Simon, Kamath, Arveen, Ibitoye, Rita, Josifova, Dragana, Wilsdon, Anna, Ross, Alison, Calder, Alistair D., Offiah, Amaka C., Wilkie, Andrew O. M., Taylor, Jenny C., and Pagnamenta, Alistair T.

Abstract

Background Current clinical testing methods used to uncover the genetic basis of rare disease have inherent limitations, which can lead to causative pathogenic variants being missed. Within the rare disease arm of the 100 000 Genomes Project (100kGP), families were recruited under the clinical indication ’single autosomal recessive mutation in rare disease’. These participants presented with strong clinical suspicion for a specific autosomal recessive disorder, but only one suspected pathogenic variant had been identified through standard-of-care testing. Whole genome sequencing (WGS) aimed to identify cryptic ’second-hit’ variants. Methods To investigate the 31 families with available data that remained unsolved following formal review within the 100kGP, SVRare was used to aggregate structural variants present in <1% of 100kGP participants. Small variants were assessed using population allele frequency data and SpliceAI. Literature searches and publicly available online tools were used for further annotation of pathogenicity. Results Using these strategies, 8/31 cases were solved, increasing the overall diagnostic yield of this cohort from 10/41 (24.4%) to 18/41 (43.9%). Exemplar cases include a patient with cystic fibrosis harbouring a novel exonic LINE1 insertion in CFTR and a patient with generalised arterial calcification of infancy with complex interlinked duplications involving exons 2–6 of ENPP1. Although ambiguous by short-read WGS, the ENPP1 variant structure was resolved using optical genome mapping and RNA analysis. Conclusion Systematic examination of cryptic variants across a multi-disease cohort successfully identifies additional pathogenic variants. WGS data analysis in autosomal recessive rare disease should consider complex structural and small intronic variants as potentially pathogenic second hits. [ABSTRACT FROM AUTHOR]

Published
2023
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41. A point mutation in the ion conduction pore of AMPA receptor GRIA3 causes dramatically perturbed sleep patterns as well as intellectual disability

Author

Davies, Benjamin, Brown, Laurence A, Cais, Ondrej, Watson, Jake, Clayton, Amber J, Chang, Veronica T, Biggs, Daniel, Preece, Christopher, Hernandez-Pliego, Polinka, Krohn, Jon, Bhomra, Amarjit, Twigg, Stephen R F, Rimmer, Andrew, Kanapin, Alexander, Sen, Arjune, Zaiwalla, Zenobia, McVean, Gil, Foster, Russell, Donnelly, Peter, Taylor, Jenny C, Blair, Edward, Nutt, David, Aricescu, Radu A, Greger, Ingo H, Peirson, Stuart N, Flint, Jonathan, and Martin, Hilary C

Published
2017
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42. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author

Palles, Claire, West, Hannah D., Chew, Edward, Galavotti, Sara, Flensburg, Christoffer, Grolleman, Judith E., Jansen, Erik A.M., Curley, Helen, Chegwidden, Laura, Arbe-Barnes, Edward H., Lander, Nicola, Truscott, Rebekah, Pagan, Judith, Bajel, Ashish, Sherwood, Kitty, Martin, Lynn, Thomas, Huw, Georgiou, Demetra, Fostira, Florentia, Goldberg, Yael, Adams, David J., van der Biezen, Simone A.M., Christie, Michael, Clendenning, Mark, Thomas, Laura E., Deltas, Constantinos, Dimovski, Aleksandar J., Dymerska, Dagmara, Lubinski, Jan, Mahmood, Khalid, van der Post, Rachel S., Sanders, Mathijs, Weitz, Jürgen, Taylor, Jenny C., Turnbull, Clare, Vreede, Lilian, van Wezel, Tom, Whalley, Celina, Arnedo-Pac, Claudia, Caravagna, Giulio, Cross, William, Chubb, Daniel, Frangou, Anna, Gruber, Andreas J., Kinnersley, Ben, Noyvert, Boris, Church, David, Graham, Trevor, Houlston, Richard, Lopez-Bigas, Nuria, Sottoriva, Andrea, Wedge, David, Jenkins, Mark A., Kuiper, Roland P., Roberts, Andrew W., Cheadle, Jeremy P., Ligtenberg, Marjolijn J.L., Hoogerbrugge, Nicoline, Koelzer, Viktor H., Rivas, Andres Dacal, Winship, Ingrid M., Ponte, Clara Ruiz, Buchanan, Daniel D., Power, Derek G., Green, Andrew, Tomlinson, Ian P.M., Sampson, Julian R., Majewski, Ian J., and de Voer, Richarda M.

Published
2022
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44. Variable skeletal phenotypes associated with biallelic variants in PRKG2

Author

Pagnamenta, Alistair T., Diaz-Gonzalez, Francisca, Banos-Pinero, Benito, Ferla, Matteo P., Toosi, Mehran B., Calder, Alistair D., Karimiani, Ehsan G., Doosti, Mohammad, Wainwright, Andrew, Wordsworth, Paul, Bailey, Kathryn, Ejeskär, Katarina, Lester, Tracy, Maroofian, Reza, Heath, Karen E., Tajsharghi, Homa, Shears, Deborah, Taylor, Jenny C., Pagnamenta, Alistair T., Diaz-Gonzalez, Francisca, Banos-Pinero, Benito, Ferla, Matteo P., Toosi, Mehran B., Calder, Alistair D., Karimiani, Ehsan G., Doosti, Mohammad, Wainwright, Andrew, Wordsworth, Paul, Bailey, Kathryn, Ejeskär, Katarina, Lester, Tracy, Maroofian, Reza, Heath, Karen E., Tajsharghi, Homa, Shears, Deborah, and Taylor, Jenny C.

Abstract

CC BY 4.0Published Online First: 15 November 2021Brief communicationThe Genomics England Research ConsortiumCorrespondence to Dr Deborah Shears; debbie.shears@ouh.nhs.uk Dr Jenny C Taylor; jenny@well.ox.ac.uk

Published
2022
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45. Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Author

Scala, Marcello, Wortmann, Saskia B., Kaya, Namik, Stellingwerff, Menno D., Pistorio, Angela, Glamuzina, Emma, van Karnebeek, Clara D., Skrypnyk, Cristina, Iwanicka-Pronicka, Katarzyna, Piekutowska-Abramczuk, Dorota, Ciara, Elżbieta, Tort, Frederic, Sheidley, Beth, Poduri, Annapurna, Jayakar, Parul, Jayakar, Anuj, Upadia, Jariya, Walano, Nicolette, Haack, Tobias B., Prokisch, Holger, Aldhalaan, Hesham, Karimiani, Ehsan G., Yildiz, Yilmaz, Ceylan, Ahmet C., Santiago-Sim, Teresa, Dameron, Amy, Yang, Hui, Toosi, Mehran B., Ashrafzadeh, Farah, Akhondian, Javad, Imannezhad, Shima, Mirzadeh, Hanieh S., Maqbool, Shazia, Farid, Aisha, Al-Muhaizea, Mohamed A., Alshwameen, Meznah O., Aldowsari, Lama, Alsagob, Maysoon, Alyousef, Ashwaq, AlMass, Rawan, AlHargan, Aljouhra, Alwadei, Ali H., AlRasheed, Maha M., Colak, Dilek, Alqudairy, Hanan, Khan, Sameena, Lines, Matthew A., García Cazorla, M. Ángeles, Ribes, Antonia, Morava, Eva, Bibi, Farah, Haider, Shahzad, Ferla, Matteo P., Taylor, Jenny C., Alsaif, Hessa S., Firdous, Abdulwahab, Hashem, Mais, Shashkin, Chingiz, Koneev, Kairgali, Kaiyrzhanov, Rauan, Efthymiou, Stephanie, Genomics, Queen Square, Schmitt-Mechelke, Thomas, Ziegler, Andreas, Issa, Mahmoud Y., Elbendary, Hasnaa M., Striano, Pasquale, Alkuraya, Fowzan S., Zaki, Maha S., Gleeson, Joseph G., Barakat, Tahsin Stefan, Bierau, Jorgen, van der Knaap, Marjo S., Maroofian, Reza, Houlden, Henry, Scala, Marcello, Wortmann, Saskia B., Kaya, Namik, Stellingwerff, Menno D., Pistorio, Angela, Glamuzina, Emma, van Karnebeek, Clara D., Skrypnyk, Cristina, Iwanicka-Pronicka, Katarzyna, Piekutowska-Abramczuk, Dorota, Ciara, Elżbieta, Tort, Frederic, Sheidley, Beth, Poduri, Annapurna, Jayakar, Parul, Jayakar, Anuj, Upadia, Jariya, Walano, Nicolette, Haack, Tobias B., Prokisch, Holger, Aldhalaan, Hesham, Karimiani, Ehsan G., Yildiz, Yilmaz, Ceylan, Ahmet C., Santiago-Sim, Teresa, Dameron, Amy, Yang, Hui, Toosi, Mehran B., Ashrafzadeh, Farah, Akhondian, Javad, Imannezhad, Shima, Mirzadeh, Hanieh S., Maqbool, Shazia, Farid, Aisha, Al-Muhaizea, Mohamed A., Alshwameen, Meznah O., Aldowsari, Lama, Alsagob, Maysoon, Alyousef, Ashwaq, AlMass, Rawan, AlHargan, Aljouhra, Alwadei, Ali H., AlRasheed, Maha M., Colak, Dilek, Alqudairy, Hanan, Khan, Sameena, Lines, Matthew A., García Cazorla, M. Ángeles, Ribes, Antonia, Morava, Eva, Bibi, Farah, Haider, Shahzad, Ferla, Matteo P., Taylor, Jenny C., Alsaif, Hessa S., Firdous, Abdulwahab, Hashem, Mais, Shashkin, Chingiz, Koneev, Kairgali, Kaiyrzhanov, Rauan, Efthymiou, Stephanie, Genomics, Queen Square, Schmitt-Mechelke, Thomas, Ziegler, Andreas, Issa, Mahmoud Y., Elbendary, Hasnaa M., Striano, Pasquale, Alkuraya, Fowzan S., Zaki, Maha S., Gleeson, Joseph G., Barakat, Tahsin Stefan, Bierau, Jorgen, van der Knaap, Marjo S., Maroofian, Reza, and Houlden, Henry

Abstract

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan–Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

Published
2022

47. Additional file 2 of Recommendations for clinical interpretation of variants found in non-coding regions of the genome

Author

Ellingford, Jamie M., Ahn, Joo Wook, Bagnall, Richard D., Baralle, Diana, Barton, Stephanie, Campbell, Chris, Downes, Kate, Ellard, Sian, Duff-Farrier, Celia, FitzPatrick, David R., Greally, John M., Ingles, Jodie, Krishnan, Neesha, Lord, Jenny, Martin, Hilary C., Newman, William G., O’Donnell-Luria, Anne, Ramsden, Simon C., Rehm, Heidi L., Richardson, Ebony, Singer-Berk, Moriel, Taylor, Jenny C., Williams, Maggie, Wood, Jordan C., Wright, Caroline F., Harrison, Steven M., and Whiffin, Nicola

Abstract

Additional file 2: Fig S1. Identifying regulatory variants in trans with pLoF variants in GEL.

Published
2022
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48. Conclusion of diagnostic odysseys due to inversions disrupting GLI3 and FBN1.

Author

Pagnamenta, Alistair T., Jing Yu, Evans, Julie, Twiss, Philip, Offiah, Amaka C., Wafik, Mohamed, Mehta, Sarju G., Javaid, Mohammed K., Smithson, Sarah F., and Taylor, Jenny C.

Abstract

Many genetic testing methodologies are biased towards picking up structural variants (SVs) that alter copy number. Copy-neutral rearrangements such as inversions are therefore likely to suffer from underascertainment. In this study, manual review prompted by a virtual multidisciplinary team meeting and subsequent bioinformatic prioritisation of data from the 100K Genomes Project was performed across 43 genes linked to well-characterised skeletal disorders. Ten individuals from three independent families were found to harbour diagnostic inversions. In two families, inverted segments of 1.2/14.8Mb unequivocally disrupted GLI3 and segregated with skeletal features consistent with Greig cephalopolysyndactyly syndrome. For one family, phenotypic blending was due to the opposing breakpoint lying ~45 kb from HOXA13. In the third family, long suspected to have Marfan syndrome, a 2.0Mb inversion disrupting FBN1 was identified. These findings resolved lengthy diagnostic odysseys of 9–20 years and highlight the importance of direct interaction between clinicians and data-analysts. These exemplars of a rare mutational class inform future SV prioritisation strategies within the NHS Genomic Medicine Service and similar genome sequencing initiatives. In over 30 years since these two disease-gene associations were identified, large inversions have yet to be described and so our results extend the mutational spectra linked to these conditions. [ABSTRACT FROM AUTHOR]

Published
2023
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49. Provocation Testing and Therapeutic Response in a Newly Described Channelopathy: RyR2 Calcium Release Deficiency Syndrome

Author

Ormerod, Julian O.M., primary, Ormondroyd, Elizabeth, additional, Li, Yanhui, additional, Taylor, John, additional, Wei, Jinhong, additional, Guo, Wenting, additional, Wang, Ruiwu, additional, Sarton, Caroline N.S., additional, McGuire, Karen, additional, Dreau, Helene M.P., additional, Taylor, Jenny C., additional, Ginks, Matthew R., additional, Rajappan, Kim, additional, Chen, S.R. Wayne, additional, and Watkins, Hugh, additional

Published
2022
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50. Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin–Siris syndrome

Author

Hempel, Annmarie, Pagnamenta, Alistair T, Blyth, Moira, Mansour, Sahar, McConnell, Vivienne, Kou, Ikuyo, Ikegawa, Shiro, Tsurusaki, Yoshinori, Matsumoto, Naomichi, Lo-Castro, Adriana, Plessis, Ghislaine, Albrecht, Beate, Battaglia, Agatino, Taylor, Jenny C, Howard, Malcolm F, Keays, David, Sohal, Aman Singh, Kühl, Susanne J, Kini, Usha, and McNeill, Alisdair

Published
2016
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