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1. Lunapark deficiency leads to an autosomal recessive neurodevelopmental phenotype with a degenerative course, epilepsy and distinct brain anomalies

Author

Accogli, Andrea, Zaki, Maha S, Al-Owain, Mohammed, Otaif, Mansour Y, Jackson, Adam, Argilli, Emanuela, Chandler, Kate E, De Goede, Christian GEL, Cora, Tülün, Alvi, Javeria Raza, Eslahi, Atieh, Asl Mohajeri, Mahsa Sadat, Ashtiani, Setareh, Au, PY Billie, Scocchia, Alicia, Alakurtti, Kirsi, Pagnamenta, Alistair T, Toosi, Mehran Beiraghi, Ghayoor Karimiani, Ehsan, Mojarrad, Majid, Arab, Fatemeh, Duymuş, Fahrettin, Scantlebury, Morris H, Yeşil, Gözde, Rosenfeld, Jill Anne, Türkyılmaz, Ayberk, Sağer, Safiye Güneş, Sultan, Tipu, Ashrafzadeh, Farah, Zahra, Tatheer, Rahman, Fatima, Maqbool, Shazia, Abdel-Hamid, Mohamed S, Issa, Mahmoud, Efthymiou, Stephanie, Bauer, Peter, Zifarelli, Giovanni, Salpietro, Vincenzo, Al-Hassnan, Zuhair, Banka, Siddharth, Sherr, Elliot H, Gleeson, Joseph G, Striano, Pasquale, Houlden, Henry, Severino, Mariasavina, and Maroofian, Reza

Subjects
Pediatric, Neurosciences, Genetics, Neurodegenerative, Clinical Research, Congenital Structural Anomalies, Brain Disorders, Rare Diseases, Human Genome, Epilepsy, 2.1 Biological and endogenous factors, Aetiology, Mental health, Neurological, Clinical sciences, Biological psychology
Abstract

Abstract: LNPK encodes a conserved membrane protein that stabilizes the junctions of the tubular endoplasmic reticulum network playing crucial roles in diverse biological functions. Recently, homozygous variants in LNPK were shown to cause a neurodevelopmental disorder (OMIM#618090) in four patients displaying developmental delay, epilepsy, and non-specific brain malformations including corpus callosum hypoplasia and variable impairment of cerebellum. We sought to delineate the molecular and phenotypic spectrum of LNPK-related disorder. Exome or genome sequencing was carried out in eleven families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified twelve distinct homozygous loss-of-function variants in sixteen individuals presenting with moderate to profound developmental delay, cognitive impairment, regression, refractory epilepsy and a recognizable neuroimaging pattern consisting of corpus callosum hypoplasia and signal alterations of the forceps minor (“ear-of-the-lynx” sign), variably associated with substantia nigra signal alterations, mild brain atrophy, short midbrain, and cerebellar hypoplasia/atrophy. In summary, we define the core phenotype of LNPK-related disorder and expand the list of neurological disorders presenting with the “ear of the lynx” sign suggesting a possible common underlying mechanism related to endoplasmic reticulum-phagy dysfunction.

Published
2023

2. Contributors

Author

Aleman, Tomas S., primary, Amati-Bonneau, Patrizia, additional, Arveiler, Benoît, additional, Ashworth, Jane L., additional, Audo, Isabelle, additional, Bacci, Giacomo M., additional, Balducci, Nicole, additional, Balikova, Irina, additional, Bauwens, Miriam, additional, Barboni, Piero, additional, Birtel, Johannes, additional, Biswas, Susmito, additional, Black, Graeme C.M., additional, Blanchet, Catherine, additional, Bocquet, Béatrice, additional, Boon, Camiel J.F., additional, Brézin, Antoine, additional, Roziers, Cyril Burin des, additional, Burkitt-Wright, Emma, additional, Callea, Michele, additional, Carbonelli, Michele, additional, Carelli, Valerio, additional, Cehajic-Kapetanovic, Jasmina, additional, Chandler, Kate E., additional, Chandra, Aman, additional, Clayton-Smith, Jill, additional, Colijn, Johanna M., additional, Coppieters, Frauke, additional, A. Cukras, Catherine, additional, Daly, Avril, additional, De Baere, Elfride, additional, De Zaeytijd, Julie, additional, Borman, Arundhati Dev, additional, Dollfus, Hélène, additional, Houge, Sofia Douzgou, additional, Engle, Elizabeth C., additional, Escher, Pascal, additional, Evans, D. Gareth, additional, Fahnehjelm, Kristina Teär, additional, Fasser, Christina, additional, Fiore, Mathieu, additional, Fujinami, Kaoru, additional, Fujinami-Yokokawa, Yu, additional, Gallie, Brenda L., additional, Georgiou, Michalis, additional, Gliem, Martin, additional, Grudzinska Pechhacker, Monika K., additional, Hall, Georgina, additional, Harmening, Wolf M., additional, Henderson, Robert H., additional, Héon, Elise, additional, Hirji, Nashila, additional, Holz, Frank G., additional, A. Huryn, Laryssa, additional, Jones, Elizabeth A., additional, Kalatzis, Vasiliki, additional, Khan, Arif O., additional, Kim, Ungsoo S., additional, Klaver, Caroline C.W., additional, Kumaran, Neruban, additional, La Morgia, Chiara, additional, Lalloo, Fiona, additional, Lasseaux, Eulalie, additional, Lee, Helena, additional, Lenaers, Guy, additional, Lenassi, Eva, additional, Leroy, Bart P., additional, Liskova, Petra, additional, Lloyd, I. Christopher, additional, MacLaren, Robert E., additional, Mahroo, Omar A., additional, Mejia-Vergara, Alvaro J., additional, Meunier, Isabelle, additional, Michaelides, Michel, additional, Moore, Anthony T., additional, Moosajee, Mariya, additional, Morice-Picard, Fanny, additional, Munier, Francis L., additional, Neveu, Magella M., additional, O'Neil, Erin C., additional, Nordenström, Anna, additional, Parry, Neil R.A., additional, Patrício, Maria I., additional, Parulekar, Manoj V., additional, Ram, Dipak, additional, Ramsden, Simon C., additional, Robitaille, Johane, additional, Robson, Anthony G., additional, Rothschild, Pierre-Raphaël, additional, Sadun, Alfredo A., additional, Schuerch, Kaspar, additional, Seabra, Miguel C., additional, Self, Jay E., additional, Sergouniotis, Panagiotis I., additional, Shaya, Fadi, additional, Sieving, Paul A., additional, Strubbe, Ine, additional, Simonelli, Francesca, additional, Small, Kent W., additional, Snead, Martin P., additional, Stepien, Karolina M., additional, Talib, Mays, additional, Taylor, Rachel L., additional, Testa, Francesco, additional, Thiadens, Alberta A.H.J., additional, Traboulsi, Elias I., additional, Tran, Viet H., additional, Vaclavik, Veronika, additional, Valleix, Sophie, additional, Van Cauwenbergh, Caroline, additional, Van Schil, Kristof, additional, Whitman, Mary C., additional, Willoughby, Colin E., additional, Xue, Kanmin, additional, Yang, Jingyan, additional, Yu-Wai-Man, Patrick, additional, Zeitz, Christina, additional, and Zinkernagel, Martin, additional

Published
2022
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5. Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14

Author

Jackson, Adam, primary, Lin, Sheng-Jia, additional, Jones, Elizabeth A., additional, Chandler, Kate E., additional, Orr, David, additional, Moss, Celia, additional, Haider, Zahra, additional, Ryan, Gavin, additional, Holden, Simon, additional, Harrison, Mike, additional, Burrows, Nigel, additional, Jones, Wendy D., additional, Loveless, Mary, additional, Petree, Cassidy, additional, Stewart, Helen, additional, Low, Karen, additional, Donnelly, Deirdre, additional, Lovell, Simon, additional, Drosou, Konstantina, additional, Varshney, Gaurav K., additional, Banka, Siddharth, additional, Ambrose, J.C., additional, Arumugam, P., additional, Bevers, R., additional, Bleda, M., additional, Boardman-Pretty, F., additional, Boustred, C.R., additional, Brittain, H., additional, Brown, M.A., additional, Caulfield, M.J., additional, Chan, G.C., additional, Giess, A., additional, Griffin, J.N., additional, Hamblin, A., additional, Henderson, S., additional, Hubbard, T.J.P., additional, Jackson, R., additional, Jones, L.J., additional, Kasperaviciute, D., additional, Kayikci, M., additional, Kousathanas, A., additional, Lahnstein, L., additional, Lakey, A., additional, Leigh, S.E.A., additional, Leong, I.U.S., additional, Lopez, F.J., additional, Maleady-Crowe, F., additional, McEntagart, M., additional, Minneci, F., additional, Mitchell, J., additional, Moutsianas, L., additional, Mueller, M., additional, Murugaesu, N., additional, Need, A.C., additional, O‘Donovan, P., additional, Odhams, C.A., additional, Patch, C., additional, Perez-Gil, D., additional, Pereira, M.B., additional, Pullinger, J., additional, Rahim, T., additional, Rendon, A., additional, Rogers, T., additional, Savage, K., additional, Sawant, K., additional, Scott, R.H., additional, Siddiq, A., additional, Sieghart, A., additional, Smith, S.C., additional, Sosinsky, A., additional, Stuckey, A., additional, Tanguy, M., additional, Taylor Tavares, A.L., additional, Thomas, E.R.A., additional, Thompson, S.R., additional, Tucci, A., additional, Welland, M.J., additional, Williams, E., additional, Witkowska, K., additional, Wood, S.M., additional, Zarowiecki, M., additional, Riess, Olaf, additional, Haack, Tobias B., additional, Graessner, Holm, additional, Zurek, Birte, additional, Ellwanger, Kornelia, additional, Ossowski, Stephan, additional, Demidov, German, additional, Sturm, Marc, additional, Schulze-Hentrich, Julia M., additional, Schüle, Rebecca, additional, Kessler, Christoph, additional, Wayand, Melanie, additional, Synofzik, Matthis, additional, Wilke, Carlo, additional, Traschütz, Andreas, additional, Schöls, Ludger, additional, Hengel, Holger, additional, Heutink, Peter, additional, Brunner, Han, additional, Scheffer, Hans, additional, Hoogerbrugge, Nicoline, additional, Hoischen, Alexander, additional, ’t Hoen, Peter A.C., additional, Vissers, Lisenka E.L.M., additional, Gilissen, Christian, additional, Steyaert, Wouter, additional, Sablauskas, Karolis, additional, de Voer, Richarda M., additional, Kamsteeg, Erik-Jan, additional, van de Warrenburg, Bart, additional, van Os, Nienke, additional, Paske, Iris te, additional, Janssen, Erik, additional, de Boer, Elke, additional, Steehouwer, Marloes, additional, Yaldiz, Burcu, additional, Kleefstra, Tjitske, additional, Brookes, Anthony J., additional, Veal, Colin, additional, Gibson, Spencer, additional, Wadsley, Marc, additional, Mehtarizadeh, Mehdi, additional, Riaz, Umar, additional, Warren, Greg, additional, Dizjikan, Farid Yavari, additional, Shorter, Thomas, additional, Töpf, Ana, additional, Straub, Volker, additional, Bettolo, Chiara Marini, additional, Specht, Sabine, additional, Clayton-Smith, Jill, additional, Alexander, Elizabeth, additional, Jackson, Adam, additional, Faivre, Laurence, additional, Thauvin, Christel, additional, Vitobello, Antonio, additional, Denommé-Pichon, Anne-Sophie, additional, Duffourd, Yannis, additional, Tisserant, Emilie, additional, Bruel, Ange-Line, additional, Peyron, Christine, additional, Pélissier, Aurore, additional, Beltran, Sergi, additional, Gut, Ivo Glynne, additional, Laurie, Steven, additional, Piscia, Davide, additional, Matalonga, Leslie, additional, Papakonstantinou, Anastasios, additional, Bullich, Gemma, additional, Corvo, Alberto, additional, Garcia, Carles, additional, Fernandez-Callejo, Marcos, additional, Hernández, Carles, additional, Picó, Daniel, additional, Paramonov, Ida, additional, Lochmüller, Hanns, additional, Gumus, Gulcin, additional, Bros-Facer, Virginie, additional, Rath, Ana, additional, Hanauer, Marc, additional, Olry, Annie, additional, Lagorce, David, additional, Havrylenko, Svitlana, additional, Izem, Katia, additional, Rigour, Fanny, additional, Stevanin, Giovanni, additional, Durr, Alexandra, additional, Davoine, Claire-Sophie, additional, Guillot-Noel, Léna, additional, Heinzmann, Anna, additional, Coarelli, Giulia, additional, Bonne, Gisèle, additional, Evangelista, Teresinha, additional, Allamand, Valérie, additional, Nelson, Isabelle, additional, Ben Yaou, Rabah, additional, Metay, Corinne, additional, Eymard, Bruno, additional, Cohen, Enzo, additional, Atalaia, Antonio, additional, Stojkovic, Tanya, additional, Macek, Milan, additional, Turnovec, Marek, additional, Thomasová, Dana, additional, Kremliková, Radka Pourová, additional, Franková, Vera, additional, Havlovicová, Markéta, additional, Kremlik, Vlastimil, additional, Parkinson, Helen, additional, Keane, Thomas, additional, Spalding, Dylan, additional, Senf, Alexander, additional, Robinson, Peter, additional, Danis, Daniel, additional, Robert, Glenn, additional, Costa, Alessia, additional, Patch, Christine, additional, Hanna, Mike, additional, Houlden, Henry, additional, Reilly, Mary, additional, Vandrovcova, Jana, additional, Muntoni, Francesco, additional, Zaharieva, Irina, additional, Sarkozy, Anna, additional, Timmerman, Vincent, additional, Baets, Jonathan, additional, Van de Vondel, Liedewei, additional, Beijer, Danique, additional, de Jonghe, Peter, additional, Nigro, Vincenzo, additional, Banfi, Sandro, additional, Torella, Annalaura, additional, Musacchia, Francesco, additional, Piluso, Giulio, additional, Ferlini, Alessandra, additional, Selvatici, Rita, additional, Rossi, Rachele, additional, Neri, Marcella, additional, Aretz, Stefan, additional, Spier, Isabel, additional, Sommer, Anna Katharina, additional, Peters, Sophia, additional, Oliveira, Carla, additional, Pelaez, Jose Garcia, additional, Matos, Ana Rita, additional, José, Celina São, additional, Ferreira, Marta, additional, Gullo, Irene, additional, Fernandes, Susana, additional, Garrido, Luzia, additional, Ferreira, Pedro, additional, Carneiro, Fátima, additional, Swertz, Morris A., additional, Johansson, Lennart, additional, van der Velde, Joeri K., additional, van der Vries, Gerben, additional, Neerincx, Pieter B., additional, Roelofs-Prins, Dieuwke, additional, Köhler, Sebastian, additional, Metcalfe, Alison, additional, Verloes, Alain, additional, Drunat, Séverine, additional, Rooryck, Caroline, additional, Trimouille, Aurelien, additional, Castello, Raffaele, additional, Morleo, Manuela, additional, Pinelli, Michele, additional, Varavallo, Alessandra, additional, De la Paz, Manuel Posada, additional, Sánchez, Eva Bermejo, additional, Martín, Estrella López, additional, Delgado, Beatriz Martínez, additional, Alonso García de la Rosa, F. Javier, additional, Ciolfi, Andrea, additional, Dallapiccola, Bruno, additional, Pizzi, Simone, additional, Radio, Francesca Clementina, additional, Tartaglia, Marco, additional, Renieri, Alessandra, additional, Benetti, Elisa, additional, Balicza, Peter, additional, Molnar, Maria Judit, additional, Maver, Ales, additional, Peterlin, Borut, additional, Münchau, Alexander, additional, Lohmann, Katja, additional, Herzog, Rebecca, additional, Pauly, Martje, additional, Macaya, Alfons, additional, Marcé-Grau, Anna, additional, Osorio, Andres Nascimiento, additional, Natera de Benito, Daniel, additional, Thompson, Rachel, additional, Polavarapu, Kiran, additional, Beeson, David, additional, Cossins, Judith, additional, Rodriguez Cruz, Pedro M., additional, Hackman, Peter, additional, Johari, Mridul, additional, Savarese, Marco, additional, Udd, Bjarne, additional, Horvath, Rita, additional, Capella, Gabriel, additional, Valle, Laura, additional, Holinski-Feder, Elke, additional, Laner, Andreas, additional, Steinke-Lange, Verena, additional, Schröck, Evelin, additional, and Rump, Andreas, additional

Published
2023
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6. Contribution of retrotransposition to developmental disorders

Author

Gardner, Eugene J., Prigmore, Elena, Gallone, Giuseppe, Danecek, Petr, Samocha, Kaitlin E., Handsaker, Juliet, Gerety, Sebastian S., Ironfield, Holly, Short, Patrick J., Sifrim, Alejandro, Singh, Tarjinder, Chandler, Kate E., Clement, Emma, Lachlan, Katherine L., Prescott, Katrina, Rosser, Elisabeth, FitzPatrick, David R., Firth, Helen V., and Hurles, Matthew E.

Published
2019
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7. Lunapark deficiency leads to an autosomal recessive neurodevelopmental phenotype with a degenerative course, epilepsy and distinct brain anomalies

Author

Accogli, Andrea, primary, Zaki, Maha S, additional, Al-Owain, Mohammed, additional, Otaif, Mansour Y, additional, Jackson, Adam, additional, Argilli, Emanuela, additional, Chandler, Kate E, additional, De Goede, Christian G E L, additional, Cora, Tülün, additional, Alvi, Javeria Raza, additional, Eslahi, Atieh, additional, Asl Mohajeri, Mahsa Sadat, additional, Ashtiani, Setareh, additional, Au, P Y Billie, additional, Scocchia, Alicia, additional, Alakurtti, Kirsi, additional, Pagnamenta, Alistair T, additional, Toosi, Mehran Beiraghi, additional, Karimiani, Ehsan Ghayoor, additional, Mojarrad, Majid, additional, Arab, Fatemeh, additional, Duymuş, Fahrettin, additional, Scantlebury, Morris H, additional, Yeşil, Gözde, additional, Rosenfeld, Jill Anne, additional, Türkyılmaz, Ayberk, additional, Sağer, Safiye Güneş, additional, Sultan, Tipu, additional, Ashrafzadeh, Farah, additional, Zahra, Tatheer, additional, Rahman, Fatima, additional, Maqbool, Shazia, additional, Abdel-Hamid, Mohamed S, additional, Issa, Mahmoud Y, additional, Efthymiou, Stephanie, additional, Bauer, Peter, additional, Zifarelli, Giovanni, additional, Salpietro, Vincenzo, additional, Al-Hassnan, Zuhair, additional, Banka, Siddharth, additional, Sherr, Elliot H, additional, Gleeson, Joseph G, additional, Striano, Pasquale, additional, Houlden, Henry, additional, Severino, Mariasavina, additional, and Maroofian, Reza, additional

Published
2023
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8. Biallelic TUFT1 variants cause woolly hair, superficial skin fragility and desmosomal defects

Author

Jackson, Adam, Moss, Celia, Chandler, Kate E, Balboa, Pablo Lopez, Bageta, Maria L, Petrof, Gabriela, Martinez, Anna E, Liu, Lu, Guy, Alyson, Mellerio, Jemima E, Lee, John Y W, Ogboli, Malobi, Ryan, Gavin, McGrath, John A, and Banka, Siddharth

Subjects
Mice, Hair Diseases/genetics, Keratinocytes/metabolism, Skin Abnormalities, Humans, Animals, Dermatology, Skin, Hair
Abstract

BackgroundDesmosomes are complex cell junction structures that connect intermediate filaments providing strong cell-to-cell adhesion in tissues exposed to mechanical stress.ObjectivesTo identify causal variants in individuals with woolly hair and skin fragility of unknown genetic cause.MethodsThis research was conducted using whole-genome sequencing, whole-exome sequencing, clinical phenotyping, haplotype analysis, single-cell RNA sequencing data analysis, immunofluorescence microscopy and transmission electron microscopy.ResultsWe identified homozygous predicted loss-of-function tuftelin-1 (TUFT1) variants in nine individuals, from three families, with woolly hair and skin fragility. One donor splice-site variant, c.60+1G>A, was present in two families, while a frameshift variant, p.Gln189Asnfs*49, was found in the third family. Haplotype analysis showed the c.60+1G>A substitution to be a founder variant in the Irish population that likely arose approximately 20 generations ago. Human and mouse single-cell RNA sequencing data showed TUFT1 expression to be enriched in the hair dermal sheath and keratinocytes. TUFT1 expression was highly correlated with genes encoding desmosomal components implicated in diseases with phenotypes that overlap with the cohort presented here. Immunofluorescence showed tuftelin-1 to be mainly localized to the peripheral cell membranes of keratinocytes in normal skin. Skin samples from individuals with TUFT1 variants showed markedly reduced immunoreactivity for tuftelin-1, with a loss of the keratinocyte cell membrane labelling. Light microscopy revealed keratinocyte adhesion, mild hyperkeratosis and areas of superficial peeling. Transmission electron microscopy showed panepidermal acantholysis with widening of intercellular spaces throughout the epidermis and desmosomal detachment through the inner plaques.ConclusionsBiallelic loss-of-function TUFT1 variants cause a new autosomal recessive skin/hair disorder characterized by woolly hair texture and early-onset skin fragility. Tuftelin-1 has a role in desmosomal integrity and function.

Published
2023

9. Prenatal Exome Sequencing Analysis in Fetal Structural Anomalies Detected by Ultrasonography (PAGE): A Cohort Study

Author

Lord, Jenny, McMullan, Dominic J., Eberhardt, Ruth Y., Rinck, Gabriele, Hamilton, Susan J., Quinlan-Jones, Elizabeth, Prigmore, Elena, Keelagher, Rebecca, Best, Sunayna K., Carey, Georgina K., Mellis, Rhiannon, Robart, Sarah, Berry, Ian R., Chandler, Kate E., Cilliers, Deirdre, Cresswell, Lara, Edwards, Sandra L., Gardiner, Carol, Henderson, Alex, Holden, Simon T., Homfray, Tessa, Lester, Tracy, Lewis, Rebecca A., Newbury-Ecob, Ruth, Prescott, Katrina, Quarrell, Oliver W., Ramsden, Simon C., Roberts, Eileen, Tapon, Dagmar, Tooley, Madeleine J., Vasudevan, Pradeep C., Weber, Astrid P., Wellesley, Diana G., Westwood, Paul, White, Helen, Parker, Michael, Williams, Denise, Jenkins, Lucy, Scott, Richard H., Kilby, Mark D., Chitty, Lyn S., Hurles, Matthew E., and Maher, Eamonn R.

Published
2019
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11. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study

Author

Rice, Gillian I, Forte, Gabriella M A, Szynkiewicz, Marcin, Chase, Diana S, Aeby, Alec, Abdel-Hamid, Mohamed S, Ackroyd, Sam, Allcock, Rebecca, Bailey, Kathryn M, Balottin, Umberto, Barnerias, Christine, Bernard, Genevieve, Bodemer, Christine, Botella, Maria P, Cereda, Cristina, Chandler, Kate E, Dabydeen, Lyvia, Dale, Russell C, De Laet, Corinne, De Goede, Christian G E L, del Toro, Mireia, Effat, Laila, Enamorado, Noemi Nunez, Fazzi, Elisa, Gener, Blanca, Haldre, Madli, Lin, Jean-Pierre S-M, Livingston, John H, Lourenco, Charles Marques, Marques, Wilson, Jr, Oades, Patrick, Peterson, Pärt, Rasmussen, Magnhild, Roubertie, Agathe, Schmidt, Johanna Loewenstein, Shalev, Stavit A, Simon, Rogelio, Spiegel, Ronen, Swoboda, Kathryn J, Temtamy, Samia A, Vassallo, Grace, Vilain, Catheline N, Vogt, Julie, Wermenbol, Vanessa, Whitehouse, William P, Soler, Doriette, Olivieri, Ivana, Orcesi, Simona, Aglan, Mona S, Zaki, Maha S, Abdel-Salam, Ghada M H, Vanderver, Adeline, Kisand, Kai, Rozenberg, Flore, Lebon, Pierre, and Crow, Yanick J

Published
2013
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13. VPS13B and Cohen Syndrome

Author

Manson, Forbes D. C., primary, Chandler, Kate E., additional, Black, Graeme C. M., additional, and Morris-Rosendahl, Deborah J., additional

Published
2016
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14. Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance

Author

Wai, Htoo A, Lord, Jenny, Lyon, Matthew, Gunning, Adam, Kelly, Hugh, Cibin, Penelope, Seaby, Eleanor G, Spiers-Fitzgerald, Kerry, Lye, Jed, Ellard, Sian, Thomas, N Simon, Bunyan, David J, Douglas, Andrew G L, Baralle, Diana, Naik, Swati, Ragge, Nicola, Cox, Helen, Morton, Jenny E., O'Driscoll, Mary, Lim, Derek, Osio, Deborah, Elmslie, Frances, Huber, Camilla, Hewitt, Julie, Brandon, Heidy, McEntagart, Meriel, Mansour, Sahar, Lahiri, Nayana, Dempsey, Esther, Manalo, Merrie, Homfray, Tessa, Saggar, Anand, Li, Jin, Barwell, Julian, Chandler, Kate E., Briggs, Tracy, Douzgou, Sofia, Adlard, Julian, Kraus, Alison, Mehta, Sarju, Watford, Amy, Donaldson, Alan, Low, Karen, Jones, Gabriela, Dixit, Abhijit, King, Elizabeth, Shannon, Nora, Kaliakatsos, Marios, Joss, Shelagh, Balasubramanian, Meena, Johnson, Diana, Everest, Sarah, Salter, Claire, Harrison, Victoria, Wise, Gillian, Torokwa, Audrey, Sands, Victoria, Pyle, Esther, Thomas, Tessy, Lachlan, Katherine, Foulds, Nicola, Lotery, Andrew, Hammans, Simon R., Pond, Emily, Horton, Rachel, Kharbanda, Mira, Hunt, David, Thomas, Charlene, Side, Lucy, Willis, Catherine, Greville-Heygate, Stephanie, Mawby, Rebecca, Mercer, Catherine, Temple, Karen, Kinning, Esther, Bojovic, Ognjen, and Archer, L.

Subjects
RNA splicing, RNA Splicing, RNA-Seq, RNA/genetics, Computational biology, Biology, exons, Article, genetic diagnosis, 03 medical and health sciences, symbols.namesake, computational biology, splice, humans, Genetics (clinical), 030304 developmental biology, Sanger sequencing, 0303 health sciences, variant interpretation, 030305 genetics & heredity, RNA, Exon skipping, Reverse transcription polymerase chain reaction, genomic medicine, Agarose gel electrophoresis, symbols, mutation, RNA-seq
Abstract

Diagnosis of genetic disorders is hampered by large numbers of variants of uncertain significance (VUSs) identified through next-generation sequencing. Many such variants may disrupt normal RNA splicing. We examined effects on splicing of a large cohort of clinically identified variants and compared performance of bioinformatic splicing prediction tools commonly used in diagnostic laboratories. Two hundred fifty-seven variants (coding and noncoding) were referred for analysis across three laboratories. Blood RNA samples underwent targeted reverse transcription polymerase chain reaction (RT-PCR) analysis with Sanger sequencing of PCR products and agarose gel electrophoresis. Seventeen samples also underwent transcriptome-wide RNA sequencing with targeted splicing analysis based on Sashimi plot visualization. Bioinformatic splicing predictions were obtained using Alamut, HSF 3.1, and SpliceAI software. Eighty-five variants (33%) were associated with abnormal splicing. The most frequent abnormality was upstream exon skipping (39/85 variants), which was most often associated with splice donor region variants. SpliceAI had greatest accuracy in predicting splicing abnormalities (0.91) and outperformed other tools in sensitivity and specificity. Splicing analysis of blood RNA identifies diagnostically important splicing abnormalities and clarifies functional effects of a significant proportion of VUSs. Bioinformatic predictions are improving but still make significant errors. RNA analysis should therefore be routinely considered in genetic disease diagnostics.

Published
2020

15. Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency

Author

Fasham, James, primary, Lin, Siying, additional, Ghosh, Promita, additional, Radio, Francesca Clementina, additional, Farrow, Emily G., additional, Thiffault, Isabelle, additional, Kussman, Jennifer, additional, Zhou, Dihong, additional, Hemming, Rick, additional, Zahka, Kenneth, additional, Chioza, Barry A., additional, Rawlins, Lettie E., additional, Wenger, Olivia K., additional, Gunning, Adam C., additional, Pizzi, Simone, additional, Onesimo, Roberta, additional, Zampino, Giuseppe, additional, Barker, Emily, additional, Osawa, Natasha, additional, Rodriguez, Megan Christine, additional, Neuhann, Teresa M., additional, Zackai, Elaine H., additional, Keena, Beth, additional, Capasso, Jenina, additional, Levin, Alex V., additional, Bhoj, Elizabeth, additional, Li, Dong, additional, Hakonarson, Hakon, additional, Wentzensen, Ingrid M., additional, Jackson, Adam, additional, Chandler, Kate E., additional, Coban-Akdemir, Zeynep H., additional, Posey, Jennifer E., additional, Banka, Siddharth, additional, Lupski, James R., additional, Sheppard, Sarah E., additional, Tartaglia, Marco, additional, Triggs-Raine, Barbara, additional, Crosby, Andrew H., additional, and Baple, Emma L., additional

Published
2021
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17. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1

Author

Crow, Yanick J., Chase, Diana S., Schmidt, Johanna Lowenstein, Szynkiewicz, Marcin, Forte, Gabriella M.A., Gornall, Hannah L., Oojageer, Anthony, Anderson, Beverley, Pizzino, Amy, Helman, Guy, Abdel-Hamid, Mohamed S., Abdel-Salam, Ghada M., Ackroyd, Sam, Aeby, Alec, Agosta, Guillermo, Albin, Catherine, Allon-Shalev, Stavit, Arellano, Montse, Ariaudo, Giada, Aswani, Vijay, Babul-Hirji, Riyana, Baildam, Eileen M., Bahi-Buisson, Nadia, Bailey, Kathryn M., Barnerias, Christine, Barth, Magalie, Battini, Roberta, Beresford, Michael W., Bernard, Geneviève, Bianchi, Marika, de Villemeur, Thierry Billette, Blair, Edward M., Bloom, Miriam, Burlina, Alberto B., Carpanelli, Maria Luisa, Carvalho, Daniel R., Castro-Gago, Manuel, Cavallini, Anna, Cereda, Cristina, Chandler, Kate E., Chitayat, David A., Collins, Abigail E., Corcoles, Concepcion Sierra, Cordeiro, Nuno J.V., Crichiutti, Giovanni, Dabydeen, Lyvia, Dale, Russell C., DArrigo, Stefano, De Goede, Christian G.E.L., De Laet, Corinne, De Waele, Liesbeth M.H., Denzler, Ines, Desguerre, Isabelle, Devriendt, Koenraad, Di Rocco, Maja, Fahey, Michael C., Fazzi, Elisa, Ferrie, Colin D., Figueiredo, António, Gener, Blanca, Goizet, Cyril, Gowrinathan, Nirmala R., Gowrishankar, Kalpana, Hanrahan, Donncha, Isidor, Bertrand, Kara, Bülent, Khan, Nasaim, King, Mary D., Kirk, Edwin P., Kumar, Ram, Lagae, Lieven, Landrieu, Pierre, Lauffer, Heinz, Laugel, Vincent, Piana, Roberta La, Lim, Ming J., Lin, Jean-Pierre S.-M., Linnankivi, Tarja, Mackay, Mark T., Marom, Daphna R., Lourenço, Charles Marques, McKee, Shane A., Moroni, Isabella, Morton, Jenny E.V., Moutard, Marie-Laure, Murray, Kevin, Nabbout, Rima, Nampoothiri, Sheela, Nunez-Enamorado, Noemi, Oades, Patrick J., Olivieri, Ivana, Ostergaard, John R., Pérez-Dueñas, Belén, Prendiville, Julie S., Ramesh, Venkateswaran, Rasmussen, Magnhild, Régal, Luc, Ricci, Federica, Rio, Marlène, Rodriguez, Diana, Roubertie, Agathe, Salvatici, Elisabetta, Segers, Karin A., Sinha, Gyanranjan P., Soler, Doriette, Spiegel, Ronen, Stödberg, Tommy I., Straussberg, Rachel, Swoboda, Kathryn J., Suri, Mohnish, Tacke, Uta, Tan, Tiong Y., te Water Naude, Johann, Teik, Keng Wee, Thomas, Maya Mary, Till, Marianne, Tonduti, Davide, Valente, Enza Maria, Van Coster, Rudy Noel, van der Knaap, Marjo S., Vassallo, Grace, Vijzelaar, Raymon, Vogt, Julie, Wallace, Geoffrey B., Wassmer, Evangeline, Webb, Hannah J., Whitehouse, William P., Whitney, Robyn N., Zaki, Maha S., Zuberi, Sameer M., Livingston, John H., Rozenberg, Flore, Lebon, Pierre, Vanderver, Adeline, Orcesi, Simona, and Rice, Gillian I.

Published
2015
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18. Personalised virtual gene panels reduce interpretation workload and maintain diagnostic rates of proband-only clinical exome sequencing for rare disorders

Author

Molina-Ramírez, Leslie Patricia, primary, Kyle, Claire, additional, Ellingford, Jamie M, additional, Wright, Ronnie, additional, Taylor, Algy, additional, Bhaskar, Sanjeev S, additional, Campbell, Christopher, additional, Jackson, Harriet, additional, Fairclough, Adele, additional, Rousseau, Abigail, additional, Burghel, George J, additional, Dutton, Laura, additional, Banka, Siddharth, additional, Briggs, Tracy A, additional, Clayton-Smith, Jill, additional, Douzgou, Sofia, additional, Jones, Elizabeth A, additional, Kingston, Helen M, additional, Kerr, Bronwyn, additional, Ealing, John, additional, Somarathi, Suresh, additional, Chandler, Kate E, additional, Stuart, Helen M, additional, Burkitt-Wright, Emma MM, additional, Newman, William G, additional, Bruce, Iain A, additional, Black, Graeme C, additional, and Gokhale, David, additional

Published
2021
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20. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Author

Radio, Francesca Clementina, primary, Pang, Kaifang, additional, Ciolfi, Andrea, additional, Levy, Michael A., additional, Hernández-García, Andrés, additional, Pedace, Lucia, additional, Pantaleoni, Francesca, additional, Liu, Zhandong, additional, de Boer, Elke, additional, Jackson, Adam, additional, Bruselles, Alessandro, additional, McConkey, Haley, additional, Stellacci, Emilia, additional, Lo Cicero, Stefania, additional, Motta, Marialetizia, additional, Carrozzo, Rosalba, additional, Dentici, Maria Lisa, additional, McWalter, Kirsty, additional, Desai, Megha, additional, Monaghan, Kristin G., additional, Telegrafi, Aida, additional, Philippe, Christophe, additional, Vitobello, Antonio, additional, Au, Margaret, additional, Grand, Katheryn, additional, Sanchez-Lara, Pedro A., additional, Baez, Joanne, additional, Lindstrom, Kristin, additional, Kulch, Peggy, additional, Sebastian, Jessica, additional, Madan-Khetarpal, Suneeta, additional, Roadhouse, Chelsea, additional, MacKenzie, Jennifer J., additional, Monteleone, Berrin, additional, Saunders, Carol J., additional, Jean Cuevas, July K., additional, Cross, Laura, additional, Zhou, Dihong, additional, Hartley, Taila, additional, Sawyer, Sarah L., additional, Monteiro, Fabíola Paoli, additional, Secches, Tania Vertemati, additional, Kok, Fernando, additional, Schultz-Rogers, Laura E., additional, Macke, Erica L., additional, Morava, Eva, additional, Klee, Eric W., additional, Kemppainen, Jennifer, additional, Iascone, Maria, additional, Selicorni, Angelo, additional, Tenconi, Romano, additional, Amor, David J., additional, Pais, Lynn, additional, Gallacher, Lyndon, additional, Turnpenny, Peter D., additional, Stals, Karen, additional, Ellard, Sian, additional, Cabet, Sara, additional, Lesca, Gaetan, additional, Pascal, Joset, additional, Steindl, Katharina, additional, Ravid, Sarit, additional, Weiss, Karin, additional, Castle, Alison M.R., additional, Carter, Melissa T., additional, Kalsner, Louisa, additional, de Vries, Bert B.A., additional, van Bon, Bregje W., additional, Wevers, Marijke R., additional, Pfundt, Rolph, additional, Stegmann, Alexander P.A., additional, Kerr, Bronwyn, additional, Kingston, Helen M., additional, Chandler, Kate E., additional, Sheehan, Willow, additional, Elias, Abdallah F., additional, Shinde, Deepali N., additional, Towne, Meghan C., additional, Robin, Nathaniel H., additional, Goodloe, Dana, additional, Vanderver, Adeline, additional, Sherbini, Omar, additional, Bluske, Krista, additional, Hagelstrom, R. Tanner, additional, Zanus, Caterina, additional, Faletra, Flavio, additional, Musante, Luciana, additional, Kurtz-Nelson, Evangeline C., additional, Earl, Rachel K., additional, Anderlid, Britt-Marie, additional, Morin, Gilles, additional, van Slegtenhorst, Marjon, additional, Diderich, Karin E.M., additional, Brooks, Alice S., additional, Gribnau, Joost, additional, Boers, Ruben G., additional, Finestra, Teresa Robert, additional, Carter, Lauren B., additional, Rauch, Anita, additional, Gasparini, Paolo, additional, Boycott, Kym M., additional, Barakat, Tahsin Stefan, additional, Graham, John M., additional, Faivre, Laurence, additional, Banka, Siddharth, additional, Wang, Tianyun, additional, Eichler, Evan E., additional, Priolo, Manuela, additional, Dallapiccola, Bruno, additional, Vissers, Lisenka E.L.M., additional, Sadikovic, Bekim, additional, Scott, Daryl A., additional, Holder, Jimmy Lloyd, additional, and Tartaglia, Marco, additional

Published
2021
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26. Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency

Author

Fasham, James, Lin, Siying, Ghosh, Promita, Radio, Francesca Clementina, Farrow, Emily G., Thiffault, Isabelle, Kussman, Jennifer, Zhou, Dihong, Hemming, Rick, Zahka, Kenneth, Chioza, Barry A., Rawlins, Lettie E., Wenger, Olivia K., Gunning, Adam C., Pizzi, Simone, Onesimo, Roberta, Zampino, Giuseppe, Barker, Emily, Osawa, Natasha, Rodriguez, Megan Christine, Neuhann, Teresa M., Zackai, Elaine H., Keena, Beth, Capasso, Jenina, Levin, Alex V., Bhoj, Elizabeth, Li, Dong, Hakonarson, Hakon, Wentzensen, Ingrid M., Jackson, Adam, Chandler, Kate E., Coban-Akdemir, Zeynep H., Posey, Jennifer E., Banka, Siddharth, Lupski, James R., Sheppard, Sarah E., Tartaglia, Marco, Triggs-Raine, Barbara, Crosby, Andrew H., and Baple, Emma L.

Abstract

We previously defined biallelic HYAL2variants causing a novel disorder in 2 families, involving orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, with Hyal2knockout mice displaying similar phenotypes. In this study, we better define the phenotype and pathologic disease mechanism.

Published
2022
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27. Personalised virtual gene panels reduce interpretation workload and maintain diagnostic rates of proband-only clinical exome sequencing for rare disorders

Author

Molina-Ramírez, Leslie Patricia, Kyle, Claire, Ellingford, Jamie M, Wright, Ronnie, Taylor, Algy, Bhaskar, Sanjeev S, Campbell, Christopher, Jackson, Harriet, Fairclough, Adele, Rousseau, Abigail, Burghel, George J, Dutton, Laura, Banka, Siddharth, Briggs, Tracy A, Clayton-Smith, Jill, Douzgou, Sofia, Jones, Elizabeth A, Kingston, Helen M, Kerr, Bronwyn, Ealing, John, Somarathi, Suresh, Chandler, Kate E, Stuart, Helen M, Burkitt-Wright, Emma MM, Newman, William G, Bruce, Iain A, Black, Graeme C, and Gokhale, David

Abstract

PurposeThe increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have assessed a clinician-led and phenotype-based approach for virtual gene panel generation for analysis of targeted CES in patients with rare disease in a single institution.MethodsRetrospective survey of 400 consecutive cases presumed by clinicians to have rare monogenic disorders, referred on singleton basis for targeted CES. We evaluated diagnostic yield and variant workload to characterise the usefulness of a clinician-led approach for generation of virtual gene panels that can incorporate up to three different phenotype-driven gene selection methods.ResultsAbnormalities of the nervous system (54.5%), including intellectual disability, head and neck (19%), skeletal system (16%), ear (15%) and eye (15%) were the most common clinical features reported in referrals. Combined phenotype-driven strategies for virtual gene panel generation were used in 57% of cases. On average, 7.3 variants (median=5) per case were retained for clinical interpretation. The overall diagnostic rate of proband-only CES using personalised phenotype-driven virtual gene panels was 24%.ConclusionsOur results show that personalised virtual gene panels are a cost-effective approach for variant analysis of CES, maintaining diagnostic yield and optimising the use of resources for clinical genomic sequencing in the clinic.

Published
2022
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28. PURA syndrome : clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

Author

Reijnders, Margot R. F., Janowski, Robert, Alvi, Mohsan, Self, Jay E., van Essen, Ton J., Vreeburg, Maaike, Rouhl, Rob P. W., Stevens, Servi J. C., Stegmann, Alexander P. A., Schieving, Jolanda, Pfundt, Rolph, van Dijk, Katinke, Smeets, Eric, Stumpel, Connie T. R. M., Bok, Levinus A., Cobben, Jan Maarten, Engelen, Marc, Mansour, Sahar, Whiteford, Margo, Chandler, Kate E., Douzgou, Sofia, Cooper, Nicola S., Tan, Ene-Choo, Foo, Roger, Lai, Angeline H. M., Rankin, Julia, Green, Andrew, Lönnqvist, Tuula, Isohanni, Pirjo, Williams, Shelley, Ruhoy, Ilene, Carvalho, Karen S., Dowling, James J., Lev, Dorit L., Sterbova, Katalin, Lassuthova, Petra, Neupauerova, Jana, Waugh, Jeff L., Keros, Sotirios, Clayton-Smith, Jill, Smithson, Sarah F., Brunner, Han G., van Hoeckel, Ceciel, Anderson, Mel, Clowes, Virginia E., Siu, Victoria Mok, Selber, Paulo, Leventer, Richard J., Nellaker, Christoffer, Niessing, Dierk, DDD Study, Clinicum, Children's Hospital, Lastenneurologian yksikkö, University of Helsinki, Research Programs Unit, Anu Wartiovaara / Principal Investigator, Research Programme for Molecular Neurology, and HUS Children and Adolescents

Subjects
ALPHA, GENES, REVEALS, 3112 Neurosciences, PATIENT, 5Q31.3 MICRODELETION SYNDROME, 3124 Neurology and psychiatry, POSTNATAL BRAIN-DEVELOPMENT
Abstract

Background De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. Objectives T o delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. Methods Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotypephenotype correlations by analysis of both recurrent mutations as well as mutation classes. Results We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. Conclusion We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

Published
2018

29. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study

Author

Lord, Jenny, primary, McMullan, Dominic J, additional, Eberhardt, Ruth Y, additional, Rinck, Gabriele, additional, Hamilton, Susan J, additional, Quinlan-Jones, Elizabeth, additional, Prigmore, Elena, additional, Keelagher, Rebecca, additional, Best, Sunayna K, additional, Carey, Georgina K, additional, Mellis, Rhiannon, additional, Robart, Sarah, additional, Berry, Ian R, additional, Chandler, Kate E, additional, Cilliers, Deirdre, additional, Cresswell, Lara, additional, Edwards, Sandra L, additional, Gardiner, Carol, additional, Henderson, Alex, additional, Holden, Simon T, additional, Homfray, Tessa, additional, Lester, Tracy, additional, Lewis, Rebecca A, additional, Newbury-Ecob, Ruth, additional, Prescott, Katrina, additional, Quarrell, Oliver W, additional, Ramsden, Simon C, additional, Roberts, Eileen, additional, Tapon, Dagmar, additional, Tooley, Madeleine J, additional, Vasudevan, Pradeep C, additional, Weber, Astrid P, additional, Wellesley, Diana G, additional, Westwood, Paul, additional, White, Helen, additional, Parker, Michael, additional, Williams, Denise, additional, Jenkins, Lucy, additional, Scott, Richard H, additional, Kilby, Mark D, additional, Chitty, Lyn S, additional, Hurles, Matthew E, additional, Maher, Eamonn R, additional, Bateman, Mark, additional, Campbell, Carolyn, additional, Campbell, Jenni, additional, Carey, Georgina, additional, Cohen, Kelly, additional, Collingwood, Emma, additional, Constantinou, Panayiotis, additional, Delmege, Catherine, additional, Ellis, Richard, additional, Evans, Jerry, additional, Everett, Thomas, additional, Pinto, Clare F, additional, Forrester, Natalie, additional, Fowler, Emma, additional, Hamilton, Susan, additional, Healey, Karen, additional, Hudson, Rebecca, additional, Lester, Tracey, additional, Lewis, Rebecca, additional, Lord, Jenny, additional, Marton, Tamas, additional, Mehta, Sarju, additional, Park, Soo-Mi, additional, Rowland, Jayne, additional, Steer, James, additional, Taylor, Emma J, additional, and Wilson, Elizabeth, additional

Published
2019
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30. ERBB4exonic deletions on chromosome 2q34 in patients with intellectual disability or epilepsy

Author

Hyder, Zerin, Van Paesschen, Wim, Sabir, Ataf, Sansbury, Francis H., Burke, Katherine B., Khan, Naz, Chandler, Kate E., Cooper, Nicola S., Wright, Ronnie, McHale, Edward, Van Esch, Hilde, and Banka, Siddharth

Abstract

ERBB4encodes the tyrosine kinase receptor HER4, a critical regulator of normal cell function and neurodevelopmental processes in the brain. One of the key ligands of HER4 is neureglin-1 (NRG1), and the HER4-NRG1 signalling pathway is essential in neural crest cell migration, and neuronal differentiation. Pharmacological inactivation of HER4 has been shown to hasten the progression of epileptogenesis in rodent models, and heterozygous ERBB4null mice are shown to have cognitive deficits and delayed motor development. Thus far there is only a single case report in the literature of a heterozygous ERBB4deletion in a patient with intellectual disability (ID). We identified nine subjects from five unrelated families with chromosome 2q34 deletions, resulting in heterozygous intragenic loss of multiple exons of ERBB4, associated with either non-syndromic ID or generalised epilepsy. In one family, the deletion segregated with ID in five affected relatives. Overall, this case series further supports that haploinsufficiency of ERBB4leads to non-syndromic intellectual disability or epilepsy.

Published
2021
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31. ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder

Author

Cuvertino, Sara, Stuart, Helen M., Chandler, Kate E., Roberts, Neil A., Armstrong, Ruth, Bernardini, Laura, Bhaskar, Sanjeev, Callewaert, Bert, Clayton-Smith, Jill, Davalillo, Cristina Hernando, Deshpande, Charu, Devriendt, Koenraad, Digilio, Maria C., Dixit, Abhijit, Edwards, Matthew, Friedman, Jan M., Gonzalez-Meneses, Antonio, Joss, Shelagh, Kerr, Bronwyn, Lampe, Anne Katrin, Langlois, Sylvie, Lennon, Rachel, Loget, Philippe, Ma, David Y. T., Mcgowan, Ruth, Des Medt, Maryse, O'Sullivan, James, Odent, Sylvie, Parker, Michael J., Pebrel-Richard, Céline, Petit, Florence, Stark, Zornitza, Stockler-Ipsiroglu, Sylvia, Tinschert, Sigrid, Vasudevan, Pradeep, Villa, Olaya, White, Susan M., Zahir, Farah R., Study, Ddd, Woolf, Adrian S., Banka, Siddharth, University of Manchester [Manchester], Regional Genetic Service, St Mary's Hospital, Manchester, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza Hospital, Center for Medical Genetics [Ghent], Ghent University Hospital, Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona]-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Guy's Hospital [London], Centre for Human Genetics, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-University Hospitals Leuven [Leuven], IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Nottingham City Hospital, Western Sydney University (UWS), University of British Columbia (UBC), Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), University of Edinburgh, Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Department of Clinical Genetics, Leicester Royal Infirmary, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Sheffield Children's Hospital, CHU Clermont-Ferrand, CHU de Lille, Genetic Health Services Victoria, Innsbruck Medical University [Austria] (IMU), University Hospitals of Leicester, University of Melbourne, Victorian Clinical Genetics Services, University of Northern British Columbia (UNBC), Hamad Bin Khalifa University (HBKU), The Wellcome Trust Sanger Institute [Cambridge], L002744/1, Medical Research Council UK, Central Manchester University Hospitals NHS Foundation Trust, Kidney Research UK, NIHR, Academy of Medical Sciences, 16-17/10, Newlife Foundation, 629396, Kabuki Research Fund, Wellcome Trust, HICF-1009-003, Health Innovation Challenge Fund, WT098051, Wellcome Trust Sanger Institute, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Western Sydney University, Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], University Hospitals Leicester-University Hospitals Leicester, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Sheffield Children's NHS Foundation Trust, University Hospitals Leicester, University of Northern British Columbia [Prince George] (UNBC), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Innsbruck Medical University = Medizinische Universität Innsbruck (IMU)

Subjects
DYNAMICS, Male, Developmental Disabilities, CYTOSKELETON, Haploinsufficiency, Mice, Medicine and Health Sciences, RNA, Small Interfering, Child, Frameshift Mutation, developmental disorder, ARCHITECTURE, Cell Cycle, Coloboma, Malformations of Cortical Development, Codon, Nonsense, Child, Preschool, DELAY, malformations, Female, RNA Interference, Abnormalities, Multiple, Adult, Adolescent, Small Interfering, Young Adult, WINTER CEREBROFRONTOFACIAL SYNDROME, Report, Intellectual Disability, Humans, Animals, Abnormalities, Multiple, MALFORMATIONS, β-actin, Preschool, Codon, Aged, Cell Proliferation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Infant, Newborn, Biology and Life Sciences, Infant, Facies, ACTB, Newborn, NUCLEAR ACTIN, Actins, BETA-ACTIN, Nonsense, DE-NOVO MUTATIONS, MECHANICS, chromatin, RNA, Gene Deletion
Abstract

ACTB encodes β-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, β-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic β-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, β-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development. ispartof: American Journal of Human Genetics vol:101 issue:6 pages:1021-1033 ispartof: location:United States status: published

Published
2017

32. PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

Author

Reijnders, Margot R F, primary, Janowski, Robert, additional, Alvi, Mohsan, additional, Self, Jay E, additional, van Essen, Ton J, additional, Vreeburg, Maaike, additional, Rouhl, Rob P W, additional, Stevens, Servi J C, additional, Stegmann, Alexander P A, additional, Schieving, Jolanda, additional, Pfundt, Rolph, additional, van Dijk, Katinke, additional, Smeets, Eric, additional, Stumpel, Connie T R M, additional, Bok, Levinus A, additional, Cobben, Jan Maarten, additional, Engelen, Marc, additional, Mansour, Sahar, additional, Whiteford, Margo, additional, Chandler, Kate E, additional, Douzgou, Sofia, additional, Cooper, Nicola S, additional, Tan, Ene-Choo, additional, Foo, Roger, additional, Lai, Angeline H M, additional, Rankin, Julia, additional, Green, Andrew, additional, Lönnqvist, Tuula, additional, Isohanni, Pirjo, additional, Williams, Shelley, additional, Ruhoy, Ilene, additional, Carvalho, Karen S, additional, Dowling, James J, additional, Lev, Dorit L, additional, Sterbova, Katalin, additional, Lassuthova, Petra, additional, Neupauerová, Jana, additional, Waugh, Jeff L, additional, Keros, Sotirios, additional, Clayton-Smith, Jill, additional, Smithson, Sarah F, additional, Brunner, Han G, additional, van Hoeckel, Ceciel, additional, Anderson, Mel, additional, Clowes, Virginia E, additional, Siu, Victoria Mok, additional, DDD study, The, additional, Selber, Paulo, additional, Leventer, Richard J, additional, Nellaker, Christoffer, additional, Niessing, Dierk, additional, Hunt, David, additional, and Baralle, Diana, additional

Published
2017
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34. Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6

Author

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

Published
2015
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35. PURA syndrome: clinical delineation and genotypephenotype study in 32 individuals with review of published literature.

Author

Reijnders, Margot R. F., Janowski, Robert, Alvi, Mohsan, Self, Jay E., van Essen, Ton J., Vreeburg, Maaike, Rouhl, Rob P. W., Stevens, Servi J. C., Stegmann, Alexander P. A., Schieving, Jolanda, Pfundt, Rolph, van Dijk, Katinke, Smeets, Eric, Stumpel, Connie T. R. M., Bok, Levinus A., Cobben, Jan Maarten, Engelen, Marc, Mansour, Sahar, Whiteford, Margo, and Chandler, Kate E.

Abstract

Background De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. Objectives T o delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. Methods Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotypephenotype correlations by analysis of both recurrent mutations as well as mutation classes. Results We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. Conclusion We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity. [ABSTRACT FROM AUTHOR]

Published
2018
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37. CRTAPmutation in a patient with Cole-Carpenter syndrome

Author

Balasubramanian, Meena, primary, Pollitt, Rebecca C., additional, Chandler, Kate E., additional, Mughal, M. Z., additional, Parker, Michael J., additional, Dalton, Ann, additional, Arundel, Paul, additional, Offiah, Amaka C., additional, and Bishop, Nicholas J., additional

Published
2015
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38. Characterization of human disease phenotypes associated with mutations inTREX1,RNASEH2A,RNASEH2B,RNASEH2C,SAMHD1,ADAR, andIFIH1

Author

Crow, Yanick J., primary, Chase, Diana S., additional, Lowenstein Schmidt, Johanna, additional, Szynkiewicz, Marcin, additional, Forte, Gabriella M.A., additional, Gornall, Hannah L., additional, Oojageer, Anthony, additional, Anderson, Beverley, additional, Pizzino, Amy, additional, Helman, Guy, additional, Abdel-Hamid, Mohamed S., additional, Abdel-Salam, Ghada M., additional, Ackroyd, Sam, additional, Aeby, Alec, additional, Agosta, Guillermo, additional, Albin, Catherine, additional, Allon-Shalev, Stavit, additional, Arellano, Montse, additional, Ariaudo, Giada, additional, Aswani, Vijay, additional, Babul-Hirji, Riyana, additional, Baildam, Eileen M., additional, Bahi-Buisson, Nadia, additional, Bailey, Kathryn M., additional, Barnerias, Christine, additional, Barth, Magalie, additional, Battini, Roberta, additional, Beresford, Michael W., additional, Bernard, Geneviève, additional, Bianchi, Marika, additional, Billette de Villemeur, Thierry, additional, Blair, Edward M., additional, Bloom, Miriam, additional, Burlina, Alberto B., additional, Luisa Carpanelli, Maria, additional, Carvalho, Daniel R., additional, Castro-Gago, Manuel, additional, Cavallini, Anna, additional, Cereda, Cristina, additional, Chandler, Kate E., additional, Chitayat, David A., additional, Collins, Abigail E., additional, Sierra Corcoles, Concepcion, additional, Cordeiro, Nuno J.V., additional, Crichiutti, Giovanni, additional, Dabydeen, Lyvia, additional, Dale, Russell C., additional, D′Arrigo, Stefano, additional, De Goede, Christian G.E.L., additional, De Laet, Corinne, additional, De Waele, Liesbeth M.H., additional, Denzler, Ines, additional, Desguerre, Isabelle, additional, Devriendt, Koenraad, additional, Di Rocco, Maja, additional, Fahey, Michael C., additional, Fazzi, Elisa, additional, Ferrie, Colin D., additional, Figueiredo, António, additional, Gener, Blanca, additional, Goizet, Cyril, additional, Gowrinathan, Nirmala R., additional, Gowrishankar, Kalpana, additional, Hanrahan, Donncha, additional, Isidor, Bertrand, additional, Kara, Bülent, additional, Khan, Nasaim, additional, King, Mary D., additional, Kirk, Edwin P., additional, Kumar, Ram, additional, Lagae, Lieven, additional, Landrieu, Pierre, additional, Lauffer, Heinz, additional, Laugel, Vincent, additional, Piana, Roberta La, additional, Lim, Ming J., additional, Lin, Jean-Pierre S.-M., additional, Linnankivi, Tarja, additional, Mackay, Mark T., additional, Marom, Daphna R., additional, Marques Lourenço, Charles, additional, McKee, Shane A., additional, Moroni, Isabella, additional, Morton, Jenny E.V., additional, Moutard, Marie-Laure, additional, Murray, Kevin, additional, Nabbout, Rima, additional, Nampoothiri, Sheela, additional, Nunez-Enamorado, Noemi, additional, Oades, Patrick J., additional, Olivieri, Ivana, additional, Ostergaard, John R., additional, Pérez-Dueñas, Belén, additional, Prendiville, Julie S., additional, Ramesh, Venkateswaran, additional, Rasmussen, Magnhild, additional, Régal, Luc, additional, Ricci, Federica, additional, Rio, Marlène, additional, Rodriguez, Diana, additional, Roubertie, Agathe, additional, Salvatici, Elisabetta, additional, Segers, Karin A., additional, Sinha, Gyanranjan P., additional, Soler, Doriette, additional, Spiegel, Ronen, additional, Stödberg, Tommy I., additional, Straussberg, Rachel, additional, Swoboda, Kathryn J., additional, Suri, Mohnish, additional, Tacke, Uta, additional, Tan, Tiong Y., additional, te Water Naude, Johann, additional, Wee Teik, Keng, additional, Mary Thomas, Maya, additional, Till, Marianne, additional, Tonduti, Davide, additional, Maria Valente, Enza, additional, Noel Van Coster, Rudy, additional, van der Knaap, Marjo S., additional, Vassallo, Grace, additional, Vijzelaar, Raymon, additional, Vogt, Julie, additional, Wallace, Geoffrey B., additional, Wassmer, Evangeline, additional, Webb, Hannah J., additional, Whitehouse, William P., additional, Whitney, Robyn N., additional, Zaki, Maha S., additional, Zuberi, Sameer M., additional, Livingston, John H., additional, Rozenberg, Flore, additional, Lebon, Pierre, additional, Vanderver, Adeline, additional, Orcesi, Simona, additional, and Rice, Gillian I., additional

Published
2015
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39. Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: A treatable neurological disorder caused by TPK1 mutations

Author

Banka, Siddharth, primary, de Goede, Christian, additional, Yue, Wyatt W., additional, Morris, Andrew A.M., additional, von Bremen, Beate, additional, Chandler, Kate E., additional, Feichtinger, René G., additional, Hart, Claire, additional, Khan, Nasaim, additional, Lunzer, Verena, additional, Mataković, Lavinija, additional, Marquardt, Thorsten, additional, Makowski, Christine, additional, Prokisch, Holger, additional, Debus, Otfried, additional, Nosaka, Kazuto, additional, Sonwalkar, Hemant, additional, Zimmermann, Franz A., additional, Sperl, Wolfgang, additional, and Mayr, Johannes A., additional

Published
2014
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40. Clinical delineation and natural history of the PIK3CA ‐related overgrowth spectrum

Author

Keppler‐Noreuil, Kim M., primary, Sapp, Julie C., additional, Lindhurst, Marjorie J., additional, Parker, Victoria E.R., additional, Blumhorst, Cathy, additional, Darling, Thomas, additional, Tosi, Laura L., additional, Huson, Susan M., additional, Whitehouse, Richard W., additional, Jakkula, Eveliina, additional, Grant, Ian, additional, Balasubramanian, Meena, additional, Chandler, Kate E., additional, Fraser, Jamie L., additional, Gucev, Zoran, additional, Crow, Yanick J., additional, Brennan, Leslie Manace, additional, Clark, Robin, additional, Sellars, Elizabeth A., additional, Pena, Loren DM, additional, Krishnamurty, Vidya, additional, Shuen, Andrew, additional, Braverman, Nancy, additional, Cunningham, Michael L., additional, Sutton, V. Reid, additional, Tasic, Velibor, additional, Graham, John M., additional, Geer, Joseph, additional, Henderson, Alex, additional, Semple, Robert K., additional, and Biesecker, Leslie G., additional

Published
2014
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41. PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

Author

Reijnders, Margot R F, Janowski, Robert, Alvi, Mohsan, Self, Jay E, van Essen, Ton J, Vreeburg, Maaike, Rouhl, Rob P W, Stevens, Servi J C, Stegmann, Alexander P A, Schieving, Jolanda, Pfundt, Rolph, van Dijk, Katinke, Smeets, Eric, Stumpel, Connie T R M, Bok, Levinus A, Cobben, Jan Maarten, Engelen, Marc, Mansour, Sahar, Whiteford, Margo, Chandler, Kate E, Douzgou, Sofia, Cooper, Nicola S, Tan, Ene-Choo, Foo, Roger, Lai, Angeline H M, Rankin, Julia, Green, Andrew, Lonnqvist, Tuula, Isohanni, Pirjo, Williams, Shelley, Ruhoy, Ilene, Carvalho, Karen S, Dowling, James J, Lev, Dorit L, Sterbova, Katalin, Lassuthova, Petra, Neupauerová, Jana, Waugh, Jeff L, Keros, Sotirios, Clayton-Smith, Jill, Smithson, Sarah F, Brunner, Han G, van Hoeckel, Ceciel, Anderson, Mel, Clowes, Virginia E, Siu, Victoria Mok, DDD study, The, Selber, Paulo, Leventer, Richard J, Nellaker, Christoffer, Niessing, Dierk, Hunt, David, and Baralle, Diana

Abstract

BackgroundDe novo mutations in PURAhave recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia.ObjectivesTo delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations.MethodsDiagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes.ResultsWe report mutations in PURA(purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes.ConclusionWe delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

Published
2018
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42. Temple Syndrome as a Result of Isolated Hypomethylation of the 14q32 Imprinted DLK1/MEG3 Region.

Author

Briggs, Tracy A., Lokulo‐Sodipe, Kemi, Chandler, Kate E., Mackay, Deborah J. G., and Temple, I. Karen

Abstract

Wepresent a Caucasian female, who was diagnosed at 13 years of age with Temple syndrome (formerly referred to as "maternal UPD 14 phenotype") due to an epigenetic loss of methylation at IG-DMR/MEG3-DMR at the chromosome 14q32 imprinted locus. Clinical features were typical and included intra-uterine growth retardation (IUGR), low birth weight, hypotonia, and poor feeding in the neonatal period; and failure to thrive and developmental delay--particularly in relation to speech--in early childhood. Premature puberty, with short stature and truncal obesity, but normal intelligence, were the key features in teenage years. To date only eight patients with Temple syndrome due to an epigenetic error have been described and the etiology of the methylation defect is currently undetermined. In view of a tendency towards central obesity, patients are at potential risk of early-onset type 2 diabetes mellitus, as well as cardiovascular disease and they, therefore, require appropriate monitoring. [ABSTRACT FROM AUTHOR]

Published
2016
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43. FOXP2variants in 14 individuals with developmental speech and language disorders broaden the mutational and clinical spectrum

Author

Reuter, Miriam S, Riess, Angelika, Moog, Ute, Briggs, Tracy A, Chandler, Kate E, Rauch, Anita, Stampfer, Miriam, Steindl, Katharina, Glaser, Dieter, Joset, Pascal, Krumbiegel, Mandy, Rabe, Harald, Schulte-Mattler, Uta, Bauer, Peter, Beck-Wodl, Stefanie, Kohlhase, Jurgen, Reis, André, and Zweier, Christiane

Abstract

BackgroundDisruptions of the FOXP2gene, encoding a forkhead transcription factor, are the first known monogenic cause of a speech and language disorder. So far, mainly chromosomal rearrangements such as translocations or larger deletions affecting FOXP2have been reported. Intragenic deletions or convincingly pathogenic point mutations in FOXP2have up to date only been reported in three families. We thus aimed at a further characterisation of the mutational and clinical spectrum.MethodsChromosomal microarray testing, trio exome sequencing, multigene panel sequencing and targeted sequencing of FOXP2were performed in individuals with variable developmental disorders, and speech and language deficits.ResultsWe identified four different truncating mutations, two novel missense mutations within the forkhead domain and an intragenic deletion in FOXP2in 14 individuals from eight unrelated families. Mutations occurred de novo in four families and were inherited from an affected parent in the other four. All index patients presented with various manifestations of language and speech impairment. Apart from two individuals with normal onset of speech, age of first words was between 4 and 7 years. Articulation difficulties such as slurred speech, dyspraxia, stuttering and poor pronunciation were frequently noted. Motor development was normal or only mildly delayed. Mild cognitive impairment was reported for most individuals.ConclusionsBy identifying intragenic deletions or mutations in 14 individuals from eight unrelated families with variable developmental delay/cognitive impairment and speech and language deficits, we considerably broaden the mutational and clinical spectrum associated with aberrations in FOXP2.

Published
2017
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44. Whole-Exome-Sequencing Identifies Mutations in Histone Acetyltransferase Gene KAT6B in Individuals with the Say-Barber-Biesecker Variant of Ohdo Syndrome

Author

Clayton-Smith, Jill, primary, O'Sullivan, James, additional, Daly, Sarah, additional, Bhaskar, Sanjeev, additional, Day, Ruth, additional, Anderson, Beverley, additional, Voss, Anne K., additional, Thomas, Tim, additional, Biesecker, Leslie G., additional, Smith, Philip, additional, Fryer, Alan, additional, Chandler, Kate E., additional, Kerr, Bronwyn, additional, Tassabehji, May, additional, Lynch, Sally-Ann, additional, Krajewska-Walasek, Malgorzata, additional, McKee, Shane, additional, Smith, Janine, additional, Sweeney, Elizabeth, additional, Mansour, Sahar, additional, Mohammed, Shehla, additional, Donnai, Dian, additional, and Black, Graeme, additional

Published
2011
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45. Mutations in PRDM5 in Brittle Cornea Syndrome Identify a Pathway Regulating Extracellular Matrix Development and Maintenance

Author

Burkitt Wright, Emma M.M., primary, Spencer, Helen L., additional, Daly, Sarah B., additional, Manson, Forbes D.C., additional, Zeef, Leo A.H., additional, Urquhart, Jill, additional, Zoppi, Nicoletta, additional, Bonshek, Richard, additional, Tosounidis, Ioannis, additional, Mohan, Meyyammai, additional, Madden, Colm, additional, Dodds, Annabel, additional, Chandler, Kate E., additional, Banka, Siddharth, additional, Au, Leon, additional, Clayton-Smith, Jill, additional, Khan, Naz, additional, Biesecker, Leslie G., additional, Wilson, Meredith, additional, Rohrbach, Marianne, additional, Colombi, Marina, additional, Giunta, Cecilia, additional, and Black, Graeme C.M., additional

Published
2011
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47. Clinical and Molecular Phenotype of Aicardi-Goutières Syndrome

Author

Rice, Gillian, primary, Patrick, Teresa, additional, Parmar, Rekha, additional, Taylor, Claire F., additional, Aeby, Alec, additional, Aicardi, Jean, additional, Artuch, Rafael, additional, Montalto, Simon Attard, additional, Bacino, Carlos A., additional, Barroso, Bruno, additional, Baxter, Peter, additional, Benko, Willam S., additional, Bergmann, Carsten, additional, Bertini, Enrico, additional, Biancheri, Roberta, additional, Blair, Edward M., additional, Blau, Nenad, additional, Bonthron, David T., additional, Briggs, Tracy, additional, Brueton, Louise A., additional, Brunner, Han G., additional, Burke, Christopher J., additional, Carr, Ian M., additional, Carvalho, Daniel R., additional, Chandler, Kate E., additional, Christen, Hans-Jürgen, additional, Corry, Peter C., additional, Cowan, Frances M., additional, Cox, Helen, additional, D’Arrigo, Stefano, additional, Dean, John, additional, De Laet, Corinne, additional, De Praeter, Claudine, additional, Déry, Catherine, additional, Ferrie, Colin D., additional, Flintoff, Kim, additional, Frints, Suzanna G.M., additional, Garcia-Cazorla, Angels, additional, Gener, Blanca, additional, Goizet, Cyril, additional, Goutières, Françoise, additional, Green, Andrew J., additional, Guët, Agnès, additional, Hamel, Ben C.J., additional, Hayward, Bruce E., additional, Heiberg, Arvid, additional, Hennekam, Raoul C., additional, Husson, Marie, additional, Jackson, Andrew P., additional, Jayatunga, Rasieka, additional, Jiang, Yong-Hui, additional, Kant, Sarina G., additional, Kao, Amy, additional, King, Mary D., additional, Kingston, Helen M., additional, Klepper, Joerg, additional, van der Knaap, Marjo S., additional, Kornberg, Andrew J., additional, Kotzot, Dieter, additional, Kratzer, Wilfried, additional, Lacombe, Didier, additional, Lagae, Lieven, additional, Landrieu, Pierre Georges, additional, Lanzi, Giovanni, additional, Leitch, Andrea, additional, Lim, Ming J., additional, Livingston, John H., additional, Lourenco, Charles M., additional, Lyall, E. G. Hermione, additional, Lynch, Sally A., additional, Lyons, Michael J., additional, Marom, Daphna, additional, McClure, John P., additional, McWilliam, Robert, additional, Melancon, Serge B., additional, Mewasingh, Leena D., additional, Moutard, Marie-Laure, additional, Nischal, Ken K., additional, Østergaard, John R., additional, Prendiville, Julie, additional, Rasmussen, Magnhild, additional, Rogers, R. Curtis, additional, Roland, Dominique, additional, Rosser, Elisabeth M., additional, Rostasy, Kevin, additional, Roubertie, Agathe, additional, Sanchis, Amparo, additional, Schiffmann, Raphael, additional, Scholl-Bürgi, Sabine, additional, Seal, Sunita, additional, Shalev, Stavit A., additional, Corcoles, C. Sierra, additional, Sinha, Gyan P., additional, Soler, Doriette, additional, Spiegel, Ronen, additional, Stephenson, John B.P., additional, Tacke, Uta, additional, Tan, Tiong Yang, additional, Till, Marianne, additional, Tolmie, John L., additional, Tomlin, Pam, additional, Vagnarelli, Federica, additional, Valente, Enza Maria, additional, Van Coster, Rudy N.A., additional, Van der Aa, Nathalie, additional, Vanderver, Adeline, additional, Vles, Johannes S.H., additional, Voit, Thomas, additional, Wassmer, Evangeline, additional, Weschke, Bernhard, additional, Whiteford, Margo L., additional, Willemsen, Michel A.A., additional, Zankl, Andreas, additional, Zuberi, Sameer M., additional, Orcesi, Simona, additional, Fazzi, Elisa, additional, Lebon, Pierre, additional, and Crow, Yanick J., additional

Published
2007
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48. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection

Author

Crow, Yanick J, primary, Leitch, Andrea, additional, Hayward, Bruce E, additional, Garner, Anna, additional, Parmar, Rekha, additional, Griffith, Elen, additional, Ali, Manir, additional, Semple, Colin, additional, Aicardi, Jean, additional, Babul-Hirji, Riyana, additional, Baumann, Clarisse, additional, Baxter, Peter, additional, Bertini, Enrico, additional, Chandler, Kate E, additional, Chitayat, David, additional, Cau, Daniel, additional, Déry, Catherine, additional, Fazzi, Elisa, additional, Goizet, Cyril, additional, King, Mary D, additional, Klepper, Joerg, additional, Lacombe, Didier, additional, Lanzi, Giovanni, additional, Lyall, Hermione, additional, Martínez-Frías, María Luisa, additional, Mathieu, Michèle, additional, McKeown, Carole, additional, Monier, Anne, additional, Oade, Yvette, additional, Quarrell, Oliver W, additional, Rittey, Christopher D, additional, Rogers, R Curtis, additional, Sanchis, Amparo, additional, Stephenson, John B P, additional, Tacke, Uta, additional, Till, Marianne, additional, Tolmie, John L, additional, Tomlin, Pam, additional, Voit, Thomas, additional, Weschke, Bernhard, additional, Woods, C Geoffrey, additional, Lebon, Pierre, additional, Bonthron, David T, additional, Ponting, Chris P, additional, and Jackson, Andrew P, additional

Published
2006
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50. Plasticity of GABA[subB] Receptor-Mediated Heterosynaptic Interactions at Mossy Fibers after Status Epilepticus.

Author

Chandler, Kate E., Princivalle, Alessandra P., Fabian-Fine, Ruth, Bowery, Norman G., Kullmann, Dimitri M., and Walker, Matthew C.

Subjects
*NEUROTRANSMITTERS, *GABA, *NEURONS, *EPILEPSY, *SYNAPSES
Abstract

Several neurotransmitters, including GABA acting at presynaptic GABA[subB] receptors, modulate glutamate release at synapses between hippocampal mossy fibers and CA3 pyramidal neurons. This phenomenon gates excitation of the hippocampus and may therefore prevent limbic seizure propagation. Here we report that status epilepticus, triggered by either perforant path stimulation or pilocarpine administration, was followed 24 hr later by a loss of GABA[subB] receptor-mediated heterosynaptic depression among populations of mossy fibers. This was accompanied by a decrease in the sensitivity of mossy fiber transmission to the exogenous GABA[subB] receptor agonist baclofen. Autoradiography revealed a reduction in GABA[subB] receptor binding in the stratum lucidum after status epilepticus. Failure of GABA[subB] receptor-mediated modulation of mossy fiber transmission at mossy fibers may contribute to the development of spontaneous seizures after status epilepticus. [ABSTRACT FROM AUTHOR]

Published
2003
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