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51. Mutations in CDC45 , Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis

Author

Fenwick, Aimee L., primary, Kliszczak, Maciej, additional, Cooper, Fay, additional, Murray, Jennie, additional, Sanchez-Pulido, Luis, additional, Twigg, Stephen R.F., additional, Goriely, Anne, additional, McGowan, Simon J., additional, Miller, Kerry A., additional, Taylor, Indira B., additional, Logan, Clare, additional, Bozdogan, Sevcan, additional, Danda, Sumita, additional, Dixon, Joanne, additional, Elsayed, Solaf M., additional, Elsobky, Ezzat, additional, Gardham, Alice, additional, Hoffer, Mariette J.V., additional, Koopmans, Marije, additional, McDonald-McGinn, Donna M., additional, Santen, Gijs W.E., additional, Savarirayan, Ravi, additional, de Silva, Deepthi, additional, Vanakker, Olivier, additional, Wall, Steven A., additional, Wilson, Louise C., additional, Yuregir, Ozge Ozalp, additional, Zackai, Elaine H., additional, Ponting, Chris P., additional, Jackson, Andrew P., additional, Wilkie, Andrew O.M., additional, Niedzwiedz, Wojciech, additional, and Bicknell, Louise S., additional

Published
2016
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52. PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution

Author

Mirzaa, Ghayda, primary, Timms, Andrew E., additional, Conti, Valerio, additional, Boyle, Evan August, additional, Girisha, Katta M., additional, Martin, Beth, additional, Kircher, Martin, additional, Olds, Carissa, additional, Juusola, Jane, additional, Collins, Sarah, additional, Park, Kaylee, additional, Carter, Melissa, additional, Glass, Ian, additional, Krägeloh-Mann, Inge, additional, Chitayat, David, additional, Parikh, Aditi Shah, additional, Bradshaw, Rachael, additional, Torti, Erin, additional, Braddock, Steve, additional, Burke, Leah, additional, Ghedia, Sondhya, additional, Stephan, Mark, additional, Stewart, Fiona, additional, Prasad, Chitra, additional, Napier, Melanie, additional, Saitta, Sulagna, additional, Straussberg, Rachel, additional, Gabbett, Michael, additional, O’Connor, Bridget C., additional, Keegan, Catherine E., additional, Yin, Lim Jiin, additional, Lai, Angeline Hwei Meeng, additional, Martin, Nicole, additional, McKinnon, Margaret, additional, Addor, Marie-Claude, additional, Boccuto, Luigi, additional, Schwartz, Charles E., additional, Lanoel, Agustina, additional, Conway, Robert L., additional, Devriendt, Koenraad, additional, Tatton-Brown, Katrina, additional, Pierpont, Mary Ella, additional, Painter, Michael, additional, Worgan, Lisa, additional, Reggin, James, additional, Hennekam, Raoul, additional, Tsuchiya, Karen, additional, Pritchard, Colin C., additional, Aracena, Mariana, additional, Gripp, Karen W., additional, Cordisco, Maria, additional, Van Esch, Hilde, additional, Garavelli, Livia, additional, Curry, Cynthia, additional, Goriely, Anne, additional, Kayserilli, Hulya, additional, Shendure, Jay, additional, Graham, John, additional, Guerrini, Renzo, additional, and Dobyns, William B., additional

Published
2016
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53. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

Author

UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, McVean, Gilean, Taylor, Jenny C., Martin, Hilary C., Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A. Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J., Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R., Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E., Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L., Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D., Goriely, Anne, Green, Angie, Greger, Ingo H., Grocock, Russell, Gruszczyk, Anja V., Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C., Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J., McMullin, Mary Frances, Miller, Kerry A., Murray, Lisa, Németh, Andrea H., Nesbit, M. Andrew, Nutt, David, Ormondroyd, Elizabeth, Bang Oturai, Annette, Pagnamenta, Alistair, Patel, Smita Y., Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E., Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A., Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, Van Schouwenburg, Pauline A., Schuh, Anna, Silverman, Earl, Simmons, Alison, Sorensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V., Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R. F., Uhlig, Holm H., Vyas, Paresh, Vyse, Tim, Wall, Steven A., Watkins, Hugh, Whyte, Michael P., Witty, Lorna, Wright, Ben, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, McVean, Gilean, Taylor, Jenny C., Martin, Hilary C., Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A. Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J., Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R., Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E., Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L., Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D., Goriely, Anne, Green, Angie, Greger, Ingo H., Grocock, Russell, Gruszczyk, Anja V., Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C., Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J., McMullin, Mary Frances, Miller, Kerry A., Murray, Lisa, Németh, Andrea H., Nesbit, M. Andrew, Nutt, David, Ormondroyd, Elizabeth, Bang Oturai, Annette, Pagnamenta, Alistair, Patel, Smita Y., Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E., Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A., Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, Van Schouwenburg, Pauline A., Schuh, Anna, Silverman, Earl, Simmons, Alison, Sorensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V., Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R. F., Uhlig, Holm H., Vyas, Paresh, Vyse, Tim, Wall, Steven A., Watkins, Hugh, Whyte, Michael P., Witty, Lorna, and Wright, Ben

Abstract

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Published
2015

54. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

Author

Taylor, Jenny C, Martin, Hilary C, Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J, Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R, Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E, Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L, Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D, Goriely, Anne, Green, Angie, Greger, Ingo H, Grocock, Russell, Gruszczyk, Anja V, Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C, Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J, McMullin, Mary Frances, Miller, Kerry A, Murray, Lisa, Németh, Andrea H, Nesbit, M Andrew, Nutt, David, Ormondroyd, Elizabeth, Oturai, Annette Bang, Pagnamenta, Alistair, Patel, Smita Y, Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E, Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A, Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, van Schouwenburg, Pauline A, Schuh, Anna, Silverman, Earl, Simmons, Alison, Sørensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V, Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R F, Uhlig, Holm H, Vyas, Paresh, Vyse, Tim, Wall, Steven A, Watkins, Hugh, Whyte, Michael P, Witty, Lorna, Wright, Ben, Yau, Chris, Buck, David, Humphray, Sean, Ratcliffe, Peter J, Bell, John I, Wilkie, Andrew O M, Bentley, David, Donnelly, Peter, McVean, Gilean, Taylor, Jenny C, Martin, Hilary C, Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J, Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R, Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E, Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L, Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D, Goriely, Anne, Green, Angie, Greger, Ingo H, Grocock, Russell, Gruszczyk, Anja V, Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C, Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J, McMullin, Mary Frances, Miller, Kerry A, Murray, Lisa, Németh, Andrea H, Nesbit, M Andrew, Nutt, David, Ormondroyd, Elizabeth, Oturai, Annette Bang, Pagnamenta, Alistair, Patel, Smita Y, Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E, Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A, Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, van Schouwenburg, Pauline A, Schuh, Anna, Silverman, Earl, Simmons, Alison, Sørensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V, Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R F, Uhlig, Holm H, Vyas, Paresh, Vyse, Tim, Wall, Steven A, Watkins, Hugh, Whyte, Michael P, Witty, Lorna, Wright, Ben, Yau, Chris, Buck, David, Humphray, Sean, Ratcliffe, Peter J, Bell, John I, Wilkie, Andrew O M, Bentley, David, Donnelly, Peter, and McVean, Gilean

Abstract

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Published
2015

55. Mutations inPIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies

Author

Ilkovski, Biljana, primary, Pagnamenta, Alistair T., additional, O'Grady, Gina L., additional, Kinoshita, Taroh, additional, Howard, Malcolm F., additional, Lek, Monkol, additional, Thomas, Brett, additional, Turner, Anne, additional, Christodoulou, John, additional, Sillence, David, additional, Knight, Samantha J.L., additional, Popitsch, Niko, additional, Keays, David A., additional, Anzilotti, Consuelo, additional, Goriely, Anne, additional, Waddell, Leigh B., additional, Brilot, Fabienne, additional, North, Kathryn N., additional, Kanzawa, Noriyuki, additional, Macarthur, Daniel G., additional, Taylor, Jenny C., additional, Kini, Usha, additional, Murakami, Yoshiko, additional, and Clarke, Nigel F., additional

Published
2015
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56. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

Author

Taylor, Jenny C, primary, Martin, Hilary C, additional, Lise, Stefano, additional, Broxholme, John, additional, Cazier, Jean-Baptiste, additional, Rimmer, Andy, additional, Kanapin, Alexander, additional, Lunter, Gerton, additional, Fiddy, Simon, additional, Allan, Chris, additional, Aricescu, A Radu, additional, Attar, Moustafa, additional, Babbs, Christian, additional, Becq, Jennifer, additional, Beeson, David, additional, Bento, Celeste, additional, Bignell, Patricia, additional, Blair, Edward, additional, Buckle, Veronica J, additional, Bull, Katherine, additional, Cais, Ondrej, additional, Cario, Holger, additional, Chapel, Helen, additional, Copley, Richard R, additional, Cornall, Richard, additional, Craft, Jude, additional, Dahan, Karin, additional, Davenport, Emma E, additional, Dendrou, Calliope, additional, Devuyst, Olivier, additional, Fenwick, Aimée L, additional, Flint, Jonathan, additional, Fugger, Lars, additional, Gilbert, Rodney D, additional, Goriely, Anne, additional, Green, Angie, additional, Greger, Ingo H, additional, Grocock, Russell, additional, Gruszczyk, Anja V, additional, Hastings, Robert, additional, Hatton, Edouard, additional, Higgs, Doug, additional, Hill, Adrian, additional, Holmes, Chris, additional, Howard, Malcolm, additional, Hughes, Linda, additional, Humburg, Peter, additional, Johnson, David, additional, Karpe, Fredrik, additional, Kingsbury, Zoya, additional, Kini, Usha, additional, Knight, Julian C, additional, Krohn, Jonathan, additional, Lamble, Sarah, additional, Langman, Craig, additional, Lonie, Lorne, additional, Luck, Joshua, additional, McCarthy, Davis, additional, McGowan, Simon J, additional, McMullin, Mary Frances, additional, Miller, Kerry A, additional, Murray, Lisa, additional, Németh, Andrea H, additional, Nesbit, M Andrew, additional, Nutt, David, additional, Ormondroyd, Elizabeth, additional, Oturai, Annette Bang, additional, Pagnamenta, Alistair, additional, Patel, Smita Y, additional, Percy, Melanie, additional, Petousi, Nayia, additional, Piazza, Paolo, additional, Piret, Sian E, additional, Polanco-Echeverry, Guadalupe, additional, Popitsch, Niko, additional, Powrie, Fiona, additional, Pugh, Chris, additional, Quek, Lynn, additional, Robbins, Peter A, additional, Robson, Kathryn, additional, Russo, Alexandra, additional, Sahgal, Natasha, additional, van Schouwenburg, Pauline A, additional, Schuh, Anna, additional, Silverman, Earl, additional, Simmons, Alison, additional, Sørensen, Per Soelberg, additional, Sweeney, Elizabeth, additional, Taylor, John, additional, Thakker, Rajesh V, additional, Tomlinson, Ian, additional, Trebes, Amy, additional, Twigg, Stephen R F, additional, Uhlig, Holm H, additional, Vyas, Paresh, additional, Vyse, Tim, additional, Wall, Steven A, additional, Watkins, Hugh, additional, Whyte, Michael P, additional, Witty, Lorna, additional, Wright, Ben, additional, Yau, Chris, additional, Buck, David, additional, Humphray, Sean, additional, Ratcliffe, Peter J, additional, Bell, John I, additional, Wilkie, Andrew O M, additional, Bentley, David, additional, Donnelly, Peter, additional, and McVean, Gilean, additional

Published
2015
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57. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors

Author

Goriely, Anne, Hansen, Ruth M S, Taylor, Indira B, Olesen, Inge A, Jacobsen, Grete Krag, McGowan, Simon J, Pfeifer, Susanne P, McVean, Gilean A T, Meyts, Ewa Rajpert-De, Wilkie, Andrew O M, Goriely, Anne, Hansen, Ruth M S, Taylor, Indira B, Olesen, Inge A, Jacobsen, Grete Krag, McGowan, Simon J, Pfeifer, Susanne P, McVean, Gilean A T, Meyts, Ewa Rajpert-De, and Wilkie, Andrew O M

Abstract

Udgivelsesdato: 2009-Nov, Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis, but the causative germline and somatic mutations occur in separate cells at different times of an organism's life. Here we unify these processes to a single cellular event for mutations arising in male germ cells that show a paternal age effect. Screening of 30 spermatocytic seminomas for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G, encoding K650E, which causes thanatophoric dysplasia in the germline) and 5 mutations in HRAS. Massively parallel sequencing of sperm DNA showed that levels of the FGFR3 mutation increase with paternal age and that the mutation spectrum at the Lys650 codon is similar to that observed in bladder cancer. Most spermatocytic seminomas show increased immunoreactivity for FGFR3 and/or HRAS. We propose that paternal age-effect mutations activate a common 'selfish' pathway supporting proliferation in the testis, leading to diverse phenotypes in the next generation including fetal lethality, congenital syndromes and cancer predisposition.

Published
2009

60. PATERNAL AGE EFFECT AND SELFISH MUTATIONS

Author

Goriely, Anne, primary, Maher, G., additional, Lim, J., additional, Taylor, I.B., additional, McGowan, S.J., additional, Pfeifer, S., additional, Rajpert-DeMeyts, E., additional, McVean, G.A.T., additional, and Wilkie, A.O.M., additional

Published
2012
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71. The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway

Author

Stevenson, David A., Schill, Lisa, Schoyer, Lisa, Andresen, Brage S., Bakker, Annette, Bayrak-Toydemir, Pinar, Burkitt-Wright, Emma, Chatfield, Kathryn, Elefteriou, Florent, Elgersma, Ype, Fisher, Michael J., Franz, David, Gelb, Bruce D., Goriely, Anne, Gripp, Karen W., Hardan, Antonio Y., Keppler-Noreuil, Kim M., Kerr, Bronwyn, Korf, Bruce, Leoni, Chiara, McCormick, Frank, Plotkin, Scott Randall, Rauen, Katherine A., Reilly, Karlyne, Roberts, Amy Elizabeth, Sandler, Abby, Siegel, Dawn, Walsh, Karin, and Widemann, Brigitte C.

Abstract

The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation–arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field.

Published
2016
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72. Munster, a novel Paired-class homeobox gene specifically expressed in the Drosophilalarval eye

Author

Goriely, Anne, Mollereau, Bertrand, Coffinier, Catherine, and Desplan, Claude

Abstract

Munster(Mu) is a homeobox-containing gene of the Paired-class which is specifically expressed in the developing Bolwig organs, the Drosophilalarval eyes. This expression is first detected during early germ band retraction stage (stage 12 from 7 h 20 at 25°C) and persists until the end of embryogenesis. Mu homeodomain is most similar to that of Aristaless and D-Goosecoid. Strikingly, the Munstergene maps within 6 kb of D-goosecoid, in the same genomic region as aristaless, suggesting that these genes are part of a homeobox gene cluster.

Published
1999
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73. The determination of sense organs in Drosophila: effect of the neurogenic mutations in the embryo

Author

Goriely, Anne, Dumont, Nathalie, Dambly-Chaudière, Christine, and Ghysen, Alain

Abstract

We have examined the early pattern of sensory mother cells in embryos mutant for six different neurogenic loci. Our results show that the neurogenic loci are required to restrict the number of competent cells that will become sensory mother cells, but are not involved in controlling the localization or the position-dependent specification of competent cells. We conclude that these loci are involved in setting up a system of mutual inhibition, which transforms graded differences within the proneural clusters into an all- or-none difference between one cell, which becomes the sense organ progenitor cell, and the other cells, which remain epidermal.

Published
1991
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74. A functional homologue of goosecoid in Drosophila

Author

Goriely, Anne, Stella, Michael, Coffinier, Catherine, Kessler, Daniel, Mailhos, Carolina, Dessain, Scott, and Desplan, Claude

Abstract

We have cloned a Drosophila homologue (D-gsc) of the ver- tebrate homeobox gene goosecoid (gsc). In the Gsc proteins, the pressure for conservation has been imposed on the homeodomain, the functional domain of the protein: sequence homology is limited to the homeodomain (78% identity) and to a short stretch of 7 aminoacids also found in other homeoproteins such as Engrailed. Despite this weak homology, D-gsc is able to mimic gsc function in a Xenopus assay, as shown by its ability to rescue the axis development of a UV-irradiated embryo. Moreover, our data suggest that the position of insect and vertebrate gsc homologues within a regulatory network has also been conserved: D-gsc expression is controlled by decapenta- plegic, orthodenticle, sloppy-paired and tailless whose homo- logues control gsc expression (for BMP4 and Otx-2), or are expressed at the right time and the right place (for XFKH1/Pintallavis and Tlx) to be interacting with gsc during vertebrate development. However, the pattern of D- gsc expression in ectodermal cells of the nervous system and foregut cannot easily be reconciled with that of ver- tebrate gsc mesodermal expression, suggesting that its precise developmental function might have diverged. Still, this comparison of domains of expression and functions among Gsc proteins could shed light on a common origin of gut formation and/or on basic cellular processes. The identification of gsc target genes and/or other genes involved in similar developmental processes will allow the definition of the precise phylogenetic relationship among Gsc proteins.

Published
1996
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75. Drosophila Goosecoid requires a conserved heptapeptide for repression of Paired-class homeoprotein activators

Author

Mailhos, Carolina, André, Sylvain, Mollereau, Bertrand, Goriely, Anne, Hemmati-Brivanlou, Ali, and Desplan, Claude

Abstract

Goosecoid (Gsc) is a homeodomain protein expressed in the organizer region of vertebrate embryos. Its Drosophila homologue, D-Gsc, has been implicated in the formation of the Stomatogastric Nervous System. Although there are no apparent similarities between the phenotypes of mutations in the gsc gene in flies and mice, all known Gsc proteins can rescue dorsoanterior structures in ventralized Xenopus embryos. We describe how D-Gsc behaves as a transcriptional repressor in Drosophila cells, acting through specific palindromic HD binding sites (P3K). D-Gsc is a ‘passive repressor’ of activator homeoproteins binding to the same sites and an ‘active repressor’ of activators binding to distinct sites. In addition, D-Gsc is able to strongly repress transcription activated by Paired-class homeoproteins through P3K, via specific protein-protein interactions in what we define as ‘interactive repression’. This form of repression requires the short conserved GEH/eh-1 domain, also present in the Engrailed repressor. Although the GEH/eh-1 domain is necessary for rescue of UV-ventralized Xenopus embryos, it is dispensable for ectopic induction of Xlim-1 expression, demonstrating that this domain is not required for all Gsc functions in vivo. Interactive repression may represent specific interactions among Prd-class homeoproteins, several of which act early during development of invertebrate and vertebrate embryos.

Published
1998
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76. Early posterior neural tissue is induced by FGF in the chick embryo

Author

Storey, Kate G., Goriely, Anne, Sargent, Catherine M., Brown, Jennifer M., Burns, Helen D., Abud, Helen M., and Heath, John K.

Abstract

Signals that induce neural cell fate in amniote embryos emanate from a unique cell population found at the anterior end of the primitive streak. Cells in this region express a number of fibroblast growth factors (FGFs), a group of secreted proteins implicated in the induction and patterning of neural tissue in the amphibian embryo. Here we exploit the large size and accessibility of the early chick embryo to analyse the function of FGF signalling specifically during neural induction. Our results demonstrate that extraembryonic epiblast cells previously shown to be responsive to endogenous neural-inducing signals express early posterior neural genes in response to local, physiological levels of FGF signal. This neural tissue does not express anterior neural markers or undergo neuronal differentiation and forms in the absence of axial mesoderm. Prospective mesodermal tissue is, however, induced and we present evidence for both the direct and indirect action of FGFs on prospective posterior neural tissue. These findings suggest that FGF signalling underlies a specific aspect of neural induction, the initiation of the programme that leads to the generation of the posterior central nervous system.

Published
1998
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77. Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes

Author

Maher, Geoffrey J, Ralph, Hannah K, Ding, Zhihao, Koelling, Nils, Mlcochova, Hana, Giannoulatou, Eleni, Dhami, Pawan, Paul, Dirk S, Stricker, Stefan H, Beck, Stephan, McVean, Gilean, Wilkie, Andrew OM, and Goriely, Anne

Subjects
Aged, 80 and over, Male, Mutation, Testis, ras Proteins, Genetic Variation, Humans, Middle Aged, Mitogen-Activated Protein Kinases, 3. Good health, Aged, Signal Transduction
Abstract

Mosaic mutations present in the germline have important implications for reproductive risk and disease transmission. We previously demonstrated a phenomenon occurring in the male germline, whereby specific mutations arising spontaneously in stem cells (spermatogonia) lead to clonal expansion, resulting in elevated mutation levels in sperm over time. This process, termed "selfish spermatogonial selection," explains the high spontaneous birth prevalence and strong paternal age-effect of disorders such as achondroplasia and Apert, Noonan and Costello syndromes, with direct experimental evidence currently available for specific positions of six genes (FGFR2, FGFR3, RET, PTPN11, HRAS, and KRAS). We present a discovery screen to identify novel mutations and genes showing evidence of positive selection in the male germline, by performing massively parallel simplex PCR using RainDance technology to interrogate mutational hotspots in 67 genes (51.5 kb in total) in 276 biopsies of testes from five men (median age, 83 yr). Following ultradeep sequencing (about 16,000×), development of a low-frequency variant prioritization strategy, and targeted validation, we identified 61 distinct variants present at frequencies as low as 0.06%, including 54 variants not previously directly associated with selfish selection. The majority (80%) of variants identified have previously been implicated in developmental disorders and/or oncogenesis and include mutations in six newly associated genes (BRAF, CBL, MAP2K1, MAP2K2, RAF1, and SOS1), all of which encode components of the RAS-MAPK pathway and activate signaling. Our findings extend the link between mutations dysregulating the RAS-MAPK pathway and selfish selection, and show that the aging male germline is a repository for such deleterious mutations.

78. Fertility preservation in pre-pubertal boys with cancer : a three-dimensional (3D) prepubertal testicular organoid culture system for in vitro spermatogonial stem cell (SSCs) propagation and spermatogenesis

Author

Tang, Shiyan, Coward, Kevin, and Goriely, Anne

Subjects
Fertility preservation
Abstract

The overall survival rate of childhood cancer has increased over the last decades due to improvements in cancer therapies. However, aggressive cancer treatments, such as chemo- or radiotherapy, can leave young prepubertal boys infertile. Cryogenically 'banking' sperm from prepubertal boys is impossible because spermatogonial stem cells (SSCs) only start to produce sperm after puberty. Thus, to help these patients preserve their fertility, it is recommended to cryopreserve their immature testicular tissues (ITTs) before receiving cancer therapies. To date, there is no standardised procedure for ITT transportation and cryopreservation in clinical practice. Approaches to fertility restoration using frozen/thawed ITTs are in the experimental stages. This thesis aimed to investigate the effects of different cryopreservation methods and potential transportation times on ITTs, and developed a three-dimensional (3D) testicular organoids (TOs) system to support the proliferation and development of SSCs. In Chapter 2, I compared the effects of uncontrolled slow freezing (USF), controlled slow freezing (CSF), and vitrification on the cryopreservation of neonatal gonocyte-containing ITTs using a bovine model. All three methods had similar effects in preserving germ cells, Sertoli cells and proliferating cells in seminiferous cords (p > 0.05). Vitrified ITTs were found to have lower cell apoptosis but higher cords-basement membrane detachment (p < 0.05). In chapter 3, I investigated the effects of transportation times of 1 hour, 6 hours, 24 hours, and 48 hours on ITTs. Transportation times up to 48 hours did not affect the viability, percentage of Sertoli cells and proliferating cells, and expressions of selected key genes (p > 0.05). However, ITTs in the 48-hour group had higher levels of deterioration in terms of the structure of the seminiferous cords (16.43%±2.14%) and decreased percentage of seminiferous cords with germ cells (43.19%±6.45%; p < 0.05). Next in Chapter 4 and chapter 5, for the first time, a 3D TO model was developed for in vitro culturing neonatal bovine testicular cells. Firstly, I optimized the dissociation and enrichment of germ cells in neonatal bovine ITTs. Next, by comparing different extracellular matrix (ECM), I found that Matrigel was optimal in the formation of germ cell aggregations. The TOs emerged from single cell suspensions and developed into 3D structures where germ cells were in the centre with Sertoli cells at the outer layers in neonatal bovine. Furthermore, growth factors glial cell line-derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF2), and leukemia inhibitory factor (LIF) were found to promote the transformation of gonocytes into SSCs, while follicle-stimulating hormone (FSH) and testosterone maintained the viability and proliferation of cells in TOs. In summary, this thesis provided evidence that vitrification could be an alternative method for cryopreservation of ITTs, and tissue transportation times of up to 24 hours does not affect tissue quality and could be used in clinical practice. In addition, a novel 3D TO system was developed in the bovine model, thus offering an in vitro platform for the propagation and development of SSCs.

Published
2022

79. Evaluating selfish spermatogonial selection and its role in human disease

Author

Ralph, Hannah Kate, Goriely, Anne, and Wilkie, Andrew

Subjects
612.6
Abstract

The majority of de novo mutations originate in the paternal germline. Prior evidence has shown that a subset of activating mutations arise spontaneously within the spermatogonial stem cell (SSC) and can expand clonally along the length of a seminiferous tubule. This process, Selfish Spermatogonial Selection (SSS), explains the high birth prevalence, and increase in frequency with paternal age, of several rare congenital disorders (e.g. Apert syndrome, achondroplasia). Quantification of these low-level mutations represents a significant technical challenge. Mutation-specific assays have been developed to assess mutation levels directly in sperm and testis samples; to date, however, only 16 loci in six genes, all of which encode members of the RAS-Mitogen-Activated Protein Kinase (RAS-MAPK) pathway, have been assessed. The aim of this thesis is to evaluate whether other mutations, genes and pathways are subject to SSS by developing scalable screening methods that allow distinction of true variation from confounding errors. My initial work focused on an existing discovery screen which utilised massively parallel droplet PCR combined with ultra-deep sequencing to assess a candidate gene panel. I undertook manual curation and targeted high-fidelity PCR to resolve a long-list of candidate variants. The validated variants display a striking overlap with clinically relevant mutations and double the number of SSS implicated genes in the RAS-MAPK pathway. Distinguishing signal from noise remains a significant challenge with PCR- based methods. To improve sensitivity, two different capture-based tech- nologies incorporating unique molecular identifiers (UMIs) were investigated. Target panels were developed to assess hotspots in candidate genes, including genes involved in cancer, intellectual disability and clonal haematopoiesis. The first mutations potentially subject to SSS outside the RAS-MAPK path- way is described, with the identification of mutations at hotspots in SMAD4, a key mediator of the TGF-β BMP signalling pathway. In summary, my work has strengthened the association of the RAS-MAPK pathway with SSS. Using refined methods to increase sensitivity and scalability, I also report the first hints that SSS may impact additional signalling processes in the testis.

Published
2018

80. Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes

Author

Hannah K Ralph, Dirk S. Paul, Nils Koelling, Pawan Dhami, Stefan H. Stricker, Geoffrey J. Maher, Hana Mlcochova, Gilean McVean, Andrew O.M. Wilkie, Stephan Beck, Anne Goriely, Eleni Giannoulatou, Zhihao Ding, McVean, Gilean [0000-0002-5012-4162], Wilkie, Andrew OM [0000-0002-2972-5481], Goriely, Anne [0000-0001-9229-7216], and Apollo - University of Cambridge Repository

Subjects
Male, Biology, medicine.disease_cause, Germline, 03 medical and health sciences, 0302 clinical medicine, Testis, medicine, Humans, HRAS, Gene, 030304 developmental biology, Aged, Genetics, Aged, 80 and over, 0303 health sciences, Mutation, Research, Genetic Variation, Middle Aged, 3. Good health, PTPN11, SOS1, ras Proteins, KRAS, Mitogen-Activated Protein Kinases, Carcinogenesis, 030217 neurology & neurosurgery, Signal Transduction
Abstract

Mosaic mutations present in the germline have important implications for reproductive risk and disease transmission. We previously demonstrated a phenomenon occurring in the male germline, whereby specific mutations arising spontaneously in stem cells (spermatogonia) lead to clonal expansion, resulting in elevated mutation levels in sperm over time. This process, termed selfish spermatogonial selection, explains the high spontaneous birth prevalence and strong paternal age-effect of disorders such as achondroplasia, Apert, Noonan and Costello syndromes, with direct experimental evidence currently available for specific positions of six genes (FGFR2, FGFR3, RET, PTPN11, HRAS and KRAS). We present a discovery screen to identify novel mutations and genes showing evidence of positive selection in the male germline, by performing massively parallel simplex PCR using RainDance technology to interrogate mutational hotspots in 67 genes (51.5 kb in total) in 276 biopsies of testes from 5 men (median age: 83 years). Following ultra-deep sequencing (~16,000x), development of a low-frequency variant prioritization strategy and targeted validation, we identified 61 distinct variants present at frequencies as low as 0.06%, including 54 variants not previously directly associated with selfish selection. The majority (80%) of variants identified have previously been implicated in developmental disorders and/or oncogenesis and include mutations in six newly associated genes (BRAF, CBL, MAP2K1, MAP2K2, RAF1 and SOS1), all of which encode components of RAS-MAPK pathway and activate signaling. Our findings extend the link between mutations dysregulating the RAS-MAPK pathway and selfish selection, and show that the ageing male germline is a repository for such deleterious mutations.

Published
2018

81. Professionals' views on providing personalized recurrence risks for de novo mutations: Implications for genetic counseling.

Author

Kay AC, Wells J, Goriely A, and Hallowell N

Abstract

When an apparent de novo (new) genetic change has been identified as the cause of a serious genetic condition in a child, many couples would like to know the risk of this happening again in a future pregnancy. Current practice provides families with a population average risk of 1%-2%. However, this figure is not accurate for any specific couple, and yet, they are asked to make decisions about having another child and/or whether to have prenatal testing. The PREcision Genetic Counseling And REproduction (PREGCARE) study is a new personalized assessment strategy that refines a couple's recurrence risk prior to a new pregnancy, by analyzing several samples from the parent-child trio (blood, saliva, swabs, and father's sperm) using deep sequencing and haplotyping. Overall, this approach can reassure ~2/3 of couples who have a negligible (<0.1%) recurrence risk and focus support on those at higher risk (i.e. when mosaicism is identified in one of the parents). Here we present a qualitative interview study with UK clinical genetics professionals (n = 20), which investigate the potential implications of introducing such a strategy in genetics clinics. While thematic analysis of the interviews indicated perceived clinical utility, it also indicates a need to prepare couples for the psychosocial implications of parent-of-origin information and to support their understanding of the assessment being offered. When dealing with personalized reproductive risk, a traditional non-directive approach may not meet the needs of practitioner and client(s) and shared decision-making provides an additional framework that may relieve some patient burden. Further qualitative investigation with couples is planned., (© 2024 The Author(s). Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Published
2024
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82. Opposing FGF and retinoid pathways control ventral neural pattern, neuronal differentiation, and segmentation during body axis extension.

Author

Diez del Corral R, Olivera-Martinez I, Goriely A, Gale E, Maden M, and Storey K

Subjects
Animals, Chick Embryo, Cleavage Stage, Ovum cytology, Cleavage Stage, Ovum metabolism, Fibroblast Growth Factor 8, Fibroblast Growth Factors genetics, Gene Expression Regulation, Developmental physiology, Humans, Mice, Neural Inhibition physiology, Neural Pathways embryology, Neural Pathways metabolism, Neurons cytology, Somites cytology, Somites metabolism, Spinal Cord cytology, Spinal Cord embryology, Cell Differentiation physiology, Fibroblast Growth Factors metabolism, Neurons metabolism, Spinal Cord metabolism, Tretinoin metabolism
Abstract

Vertebrate body axis extension involves progressive generation and subsequent differentiation of new cells derived from a caudal stem zone; however, molecular mechanisms that preserve caudal progenitors and coordinate differentiation are poorly understood. FGF maintains caudal progenitors and its attenuation is required for neuronal and mesodermal differentiation and to position segment boundaries. Furthermore, somitic mesoderm promotes neuronal differentiation in part by downregulating Fgf8. Here we identify retinoic acid (RA) as this somitic signal and show that retinoid and FGF pathways have opposing actions. FGF is a general repressor of differentiation, including ventral neural patterning, while RA attenuates Fgf8 in neuroepithelium and paraxial mesoderm, where it controls somite boundary position. RA is further required for neuronal differentiation and expression of key ventral neural patterning genes. Our data demonstrate that FGF and RA pathways are mutually inhibitory and suggest that their opposing actions provide a global mechanism that controls differentiation during axis extension.

Published
2003
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