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1. Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author

Kast, Karin, John, Esther M., Hopper, John L., Andrieu, Nadine, Noguès, Catherine, Mouret-Fourme, Emmanuelle, Lasset, Christine, Fricker, Jean-Pierre, Berthet, Pascaline, Mari, Véronique, Salle, Lucie, Schmidt, Marjanka K., Ausems, Margreet G. E. M., Garcia, Encarnacion B. Gomez, van de Beek, Irma, Wevers, Marijke R., Evans, D. Gareth, Tischkowitz, Marc, Lalloo, Fiona, Cook, Jackie, Izatt, Louise, Tripathi, Vishakha, Snape, Katie, Musgrave, Hannah, Sharif, Saba, Murray, Jennie, Colonna, Sarah V., Andrulis, Irene L., Daly, Mary B., Southey, Melissa C., de la Hoya, Miguel, Osorio, Ana, Foretova, Lenka, Berkova, Dita, Gerdes, Anne-Marie, Olah, Edith, Jakubowska, Anna, Singer, Christian F., Tan, Yen, Augustinsson, Annelie, Rantala, Johanna, Simard, Jacques, Schmutzler, Rita K., Milne, Roger L., Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David, van Leeuwen, Flora E., Mooij, Thea M., Antoniou, Antonis C., Easton, Douglas F., Rookus, Matti A., and Engel, Christoph

Published
2023
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4. Expanding the genetics of microcephalic primordial dwarfism

Author

Murray, Jennie Elaine and Jackson, Andrew

Subjects
616.4, growth, primordial dwarfism, exome sequencing, LIG4, XRCC4, condensin
Abstract

Body mass varies considerably between different mammals and this variation is largely accounted for by a difference in total cell number rather than individual cell size. Insights into mechanisms regulating growth can therefore be gained by understanding what governs total cell number at any one point. In addition, control of cell proliferation and programmed cell death is fundamental to other areas of research such as cancer and stem cell research. Microcephalic Primordial Dwarfism (MPD) is a group of rare Mendelian human disorders in which there is an extreme global failure of growth with affected individuals often only reaching a height of around one metre in adulthood. To date, all identified disease genes follow an autosomal recessive mode of inheritance and encode key regulators of the cell cycle, where mutations impact on overall cell number and result in a substantially reduced body size. MPD therefore provides a valuable model for examining genetic and cellular mechanisms that impact on growth. The overall aims of this thesis were to identify novel disease causing genes, as well as provide further characterisation of known disease causing genes, through the analysis of whole exome sequencing (WES) within a large cohort of MPD patients. Following the design and implementation of an analytical bioinformatics pipeline, deleterious mutations were identified in multiple disease genes including LIG4 and XRCC4. Both genes encode components of the non-homologous end joining machinery, a DNA repair mechanism not previously implicated in MPD. Additionally, the pathogenicity of novel mutations in subunits of a protein complex involved in chromosome segregation was assessed using patient-derived cells. These findings demonstrate WES can be successfully implemented to identify known and novel disease causing genes within a large heterogeneous cohort of patients, expanding the phenotype of known disorders and improving diagnosis as well as providing novel insights into intrinsic cellular mechanisms critical to growth.

Published
2015

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

Author

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

Published
2016
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6. Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome

Author

Lalloo, Fiona, Kulkarni, Anju, Chau, Cindy, Nielsen, Maartje, Sheaff, Michael, Steele, Jeremy, van Doorn, Remco, Wadt, Karin, Hamill, Monica, Torr, Beth, Tischkowitz, Marc, Ahmed, Munaza, Bajalica-Lagercrantz, Svetlana, Blatnik, Ana, Brunet, Joan, Cleaver, Ruth, Colas, Chrystelle, Dabir, Tabib, Evans, D. Gareth, Feshtali, Shirin, Ghiorzo, Paola, Graversen, Lise, Griewank, Klaus, Helgadottir, Hildur, Jewell, Rosalyn, Kohut, Kelly, Lorentzen, Henrik, Massi, Daniela, Missotten, Guy, Murray, Alex, Murray, Jennie, Nadal, Ernest, Ong, Kai Ren, Piulats, Josep M., Puig, Susana, Rajan, Neil, Ribero, Simone, Salle, Galateau, Teulé, Alexandre, Tham, Emma, van Paassen, Barbara, De Putter, Robin, Verdijk, Robert, Wagner, Anja, Woodward, Emma R., Hanson, Helen, Lalloo, Fiona, Kulkarni, Anju, Chau, Cindy, Nielsen, Maartje, Sheaff, Michael, Steele, Jeremy, van Doorn, Remco, Wadt, Karin, Hamill, Monica, Torr, Beth, Tischkowitz, Marc, Ahmed, Munaza, Bajalica-Lagercrantz, Svetlana, Blatnik, Ana, Brunet, Joan, Cleaver, Ruth, Colas, Chrystelle, Dabir, Tabib, Evans, D. Gareth, Feshtali, Shirin, Ghiorzo, Paola, Graversen, Lise, Griewank, Klaus, Helgadottir, Hildur, Jewell, Rosalyn, Kohut, Kelly, Lorentzen, Henrik, Massi, Daniela, Missotten, Guy, Murray, Alex, Murray, Jennie, Nadal, Ernest, Ong, Kai Ren, Piulats, Josep M., Puig, Susana, Rajan, Neil, Ribero, Simone, Salle, Galateau, Teulé, Alexandre, Tham, Emma, van Paassen, Barbara, De Putter, Robin, Verdijk, Robert, Wagner, Anja, Woodward, Emma R., and Hanson, Helen

Abstract

BRCA1-associated protein-1 (BAP1) is a recognised tumour suppressor gene. Germline BAP1 pathogenic/likely pathogenic variants are associated with predisposition to multiple tumours, including uveal melanoma, malignant pleural and peritoneal mesothelioma, renal cell carcinoma and specific non-malignant neoplasms of the skin, as part of the autosomal dominant BAP1-tumour predisposition syndrome. The overall lifetime risk for BAP1 carriers to develop at least one BAP1-associated tumour is up to 85%, although due to ascertainment bias, current estimates of risk are likely to be overestimated. As for many rare cancer predisposition syndromes, there is limited scientific evidence to support the utility of surveillance and, therefore, management recommendations for BAP1 carriers are based on expert opinion. To date, European recommendations for BAP1 carriers have not been published but are necessary due to the emerging phenotype of this recently described syndrome and increased identification of BAP1 carriers via large gene panels or tumour sequencing. To address this, the Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom invited European collaborators to collaborate to develop guidelines to harmonize surveillance programmes within Europe. Recommendations with respect to BAP1 testing and surveillance were achieved following literature review and Delphi survey completed by a core group and an extended expert group of 34 European specialists including Geneticists, Ophthalmologists, Oncologists, Dermatologists and Pathologists. It is recognised that these largely evidence-based but pragmatic recommendations will evolve over time as further data from research collaborations informs the phenotypic spectrum and surveillance outcomes.

Published
2023

7. Mutations in the NHEJ Component XRCC4 Cause Primordial Dwarfism

Author

Murray, Jennie E., van der Burg, Mirjam, IJspeert, Hanna, Carroll, Paula, Wu, Qian, Ochi, Takashi, Leitch, Andrea, Miller, Edward S., Kysela, Boris, Jawad, Alireza, Bottani, Armand, Brancati, Francesco, Cappa, Marco, Cormier-Daire, Valerie, Deshpande, Charu, Faqeih, Eissa A., Graham, Gail E., Ranza, Emmanuelle, Blundell, Tom L., Jackson, Andrew P., Stewart, Grant S., and Bicknell, Louise S.

Published
2015
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8. Additional file 2 of Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author

Kast, Karin, John, Esther M., Hopper, John L., Andrieu, Nadine, Noguès, Catherine, Mouret-Fourme, Emmanuelle, Lasset, Christine, Fricker, Jean-Pierre, Berthet, Pascaline, Mari, Véronique, Salle, Lucie, Schmidt, Marjanka K., Ausems, Margreet G. E. M., Garcia, Encarnacion B. Gomez, van de Beek, Irma, Wevers, Marijke R., Evans, D. Gareth, Tischkowitz, Marc, Lalloo, Fiona, Cook, Jackie, Izatt, Louise, Tripathi, Vishakha, Snape, Katie, Musgrave, Hannah, Sharif, Saba, Murray, Jennie, Colonna, Sarah V., Andrulis, Irene L., Daly, Mary B., Southey, Melissa C., de la Hoya, Miguel, Osorio, Ana, Foretova, Lenka, Berkova, Dita, Gerdes, Anne-Marie, Olah, Edith, Jakubowska, Anna, Singer, Christian F., Tan, Yen, Augustinsson, Annelie, Rantala, Johanna, Simard, Jacques, Schmutzler, Rita K., Milne, Roger L., Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David, van Leeuwen, Flora E., Mooij, Thea M., Antoniou, Antonis C., Easton, Douglas F., Rookus, Matti A., and Engel, Christoph

Abstract

Additional file 2: Table S2. Retrospective and prospective analysis of height in quintiles and breast cancer risk, by menopausal status.

Published
2023
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9. Additional file 3 of Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author

Kast, Karin, John, Esther M., Hopper, John L., Andrieu, Nadine, Noguès, Catherine, Mouret-Fourme, Emmanuelle, Lasset, Christine, Fricker, Jean-Pierre, Berthet, Pascaline, Mari, Véronique, Salle, Lucie, Schmidt, Marjanka K., Ausems, Margreet G. E. M., Garcia, Encarnacion B. Gomez, van de Beek, Irma, Wevers, Marijke R., Evans, D. Gareth, Tischkowitz, Marc, Lalloo, Fiona, Cook, Jackie, Izatt, Louise, Tripathi, Vishakha, Snape, Katie, Musgrave, Hannah, Sharif, Saba, Murray, Jennie, Colonna, Sarah V., Andrulis, Irene L., Daly, Mary B., Southey, Melissa C., de la Hoya, Miguel, Osorio, Ana, Foretova, Lenka, Berkova, Dita, Gerdes, Anne-Marie, Olah, Edith, Jakubowska, Anna, Singer, Christian F., Tan, Yen, Augustinsson, Annelie, Rantala, Johanna, Simard, Jacques, Schmutzler, Rita K., Milne, Roger L., Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David, van Leeuwen, Flora E., Mooij, Thea M., Antoniou, Antonis C., Easton, Douglas F., Rookus, Matti A., and Engel, Christoph

Abstract

Additional file 3: Table S3. Retrospective analysis of height, body mass index, weight change and breast cancer risk, by menopausal status.

Published
2023
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10. Additional file 1 of Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author

Kast, Karin, John, Esther M., Hopper, John L., Andrieu, Nadine, Noguès, Catherine, Mouret-Fourme, Emmanuelle, Lasset, Christine, Fricker, Jean-Pierre, Berthet, Pascaline, Mari, Véronique, Salle, Lucie, Schmidt, Marjanka K., Ausems, Margreet G. E. M., Garcia, Encarnacion B. Gomez, van de Beek, Irma, Wevers, Marijke R., Evans, D. Gareth, Tischkowitz, Marc, Lalloo, Fiona, Cook, Jackie, Izatt, Louise, Tripathi, Vishakha, Snape, Katie, Musgrave, Hannah, Sharif, Saba, Murray, Jennie, Colonna, Sarah V., Andrulis, Irene L., Daly, Mary B., Southey, Melissa C., de la Hoya, Miguel, Osorio, Ana, Foretova, Lenka, Berkova, Dita, Gerdes, Anne-Marie, Olah, Edith, Jakubowska, Anna, Singer, Christian F., Tan, Yen, Augustinsson, Annelie, Rantala, Johanna, Simard, Jacques, Schmutzler, Rita K., Milne, Roger L., Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David, van Leeuwen, Flora E., Mooij, Thea M., Antoniou, Antonis C., Easton, Douglas F., Rookus, Matti A., and Engel, Christoph

Abstract

Additional file 1: Table S1. Overview of the studies contributing to the retrospective and prospective analyses.

Published
2023
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11. Additional file 5 of Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author

Kast, Karin, John, Esther M., Hopper, John L., Andrieu, Nadine, Noguès, Catherine, Mouret-Fourme, Emmanuelle, Lasset, Christine, Fricker, Jean-Pierre, Berthet, Pascaline, Mari, Véronique, Salle, Lucie, Schmidt, Marjanka K., Ausems, Margreet G. E. M., Garcia, Encarnacion B. Gomez, van de Beek, Irma, Wevers, Marijke R., Evans, D. Gareth, Tischkowitz, Marc, Lalloo, Fiona, Cook, Jackie, Izatt, Louise, Tripathi, Vishakha, Snape, Katie, Musgrave, Hannah, Sharif, Saba, Murray, Jennie, Colonna, Sarah V., Andrulis, Irene L., Daly, Mary B., Southey, Melissa C., de la Hoya, Miguel, Osorio, Ana, Foretova, Lenka, Berkova, Dita, Gerdes, Anne-Marie, Olah, Edith, Jakubowska, Anna, Singer, Christian F., Tan, Yen, Augustinsson, Annelie, Rantala, Johanna, Simard, Jacques, Schmutzler, Rita K., Milne, Roger L., Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David, van Leeuwen, Flora E., Mooij, Thea M., Antoniou, Antonis C., Easton, Douglas F., Rookus, Matti A., and Engel, Christoph

Abstract

Additional file 5: Table S5. Weight versus body mass index and breast cancer risk in BRCA1 and BRCA2 variant carriers, by menopausal status.

Published
2023
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12. Additional file 4 of Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author

Kast, Karin, John, Esther M., Hopper, John L., Andrieu, Nadine, Noguès, Catherine, Mouret-Fourme, Emmanuelle, Lasset, Christine, Fricker, Jean-Pierre, Berthet, Pascaline, Mari, Véronique, Salle, Lucie, Schmidt, Marjanka K., Ausems, Margreet G. E. M., Garcia, Encarnacion B. Gomez, van de Beek, Irma, Wevers, Marijke R., Evans, D. Gareth, Tischkowitz, Marc, Lalloo, Fiona, Cook, Jackie, Izatt, Louise, Tripathi, Vishakha, Snape, Katie, Musgrave, Hannah, Sharif, Saba, Murray, Jennie, Colonna, Sarah V., Andrulis, Irene L., Daly, Mary B., Southey, Melissa C., de la Hoya, Miguel, Osorio, Ana, Foretova, Lenka, Berkova, Dita, Gerdes, Anne-Marie, Olah, Edith, Jakubowska, Anna, Singer, Christian F., Tan, Yen, Augustinsson, Annelie, Rantala, Johanna, Simard, Jacques, Schmutzler, Rita K., Milne, Roger L., Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David, van Leeuwen, Flora E., Mooij, Thea M., Antoniou, Antonis C., Easton, Douglas F., Rookus, Matti A., and Engel, Christoph

Abstract

Additional file 4: Table S4. Prospective analysis of associations between height, body mass index, weight change and breast cancer risk, by menopausal status.

Published
2023
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14. UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2.

Author

Hanson, Helen, Kulkarni, Anjana, Loong, Lucy, Kavanaugh, Grace, Torr, Bethany, Allen, Sophie, Ahmed, Munaza, Antoniou, Antonis C., Cleaver, Ruth, Dabir, Tabib, Gareth Evans, D., Golightly, Ellen, Jewell, Rosalyn, Kohut, Kelly, Manchanda, Ranjit, Murray, Alex, Murray, Jennie, Ong, Kai-Ren, Rosenthal, Adam N., and Woodward, Emma Roisin

Abstract

Germline pathogenic variants (GPVs) in the cancer predisposition genes BRCA1, BRCA2, MLH1, MSH2, MSH6, BRIP1, PALB2, RAD51D and RAD51C are identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV in BRCA1, BRCA2, MLH1, MSH2 and MSH6, there are few guidelines on how to manage the more moderate OC risk in patients with GPV in BRIP1, PALB2, RAD51D and RAD51C, with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of RAD51C and RAD51D as OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients with non-mucinous OC, new data on BC risk and improved estimates of OC risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a 2-day meeting to reach a national consensus on clinical management of BRIP1, PALB2, RAD51D and RAD51C carriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree on a consensus, as well as the key recommendations from the meeting. [ABSTRACT FROM AUTHOR]

Published
2023
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15. UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1and PALB2

Author

Hanson, Helen, Kulkarni, Anjana, Loong, Lucy, Kavanaugh, Grace, Torr, Bethany, Allen, Sophie, Ahmed, Munaza, Antoniou, Antonis C, Cleaver, Ruth, Dabir, Tabib, Evans, D Gareth, Golightly, Ellen, Jewell, Rosalyn, Kohut, Kelly, Manchanda, Ranjit, Murray, Alex, Murray, Jennie, Ong, Kai-Ren, Rosenthal, Adam N, Woodward, Emma Roisin, Eccles, Diana M, Turnbull, Clare, Tischkowitz, Marc, and Lalloo, Fiona

Abstract

Germline pathogenic variants (GPVs) in the cancer predisposition genes BRCA1, BRCA2, MLH1, MSH2, MSH6, BRIP1, PALB2, RAD51Dand RAD51Care identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV in BRCA1, BRCA2, MLH1, MSH2and MSH6, there are few guidelines on how to manage the more moderate OC risk in patients with GPV in BRIP1, PALB2, RAD51Dand RAD51C, with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of RAD51Cand RAD51Das OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients with non-mucinous OC, new data on BC risk and improved estimates of OC risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a 2-day meeting to reach a national consensus on clinical management of BRIP1, PALB2, RAD51Dand RAD51Ccarriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree on a consensus, as well as the key recommendations from the meeting.

Published
2023
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16. DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency

Author

Aitman, Timothy J., Biankin, Andrew V., Cooke, Susanna L., Humphrey, Wendy Inglis, Martin, Sancha, Mennie, Lynne, Meynert, Alison, Miedzybrodzka, Zosia, Murphy, Fiona, Nourse, Craig, Santoyo-Lopez, Javier, Semple, Colin A., Williams, Nicola, Logan, Clare V., Murray, Jennie E., Parry, David A., Robertson, Andrea, Bellelli, Roberto, Tarnauskaitė, Žygimantė, Challis, Rachel, Cleal, Louise, Borel, Valerie, Fluteau, Adeline, Aitman, Tim, Barroso, Inês, Basel, Donald, Bicknell, Louise S., Goel, Himanshu, Hu, Hao, Huff, Chad, Hutchison, Michele, Joyce, Caroline, Knox, Rachel, Lacroix, Amy E., Langlois, Sylvie, McCandless, Shawn, McCarrier, Julie, Metcalfe, Kay A., Morrissey, Rose, Murphy, Nuala, Netchine, Irène, O’Connell, Susan M., Olney, Ann Haskins, Paria, Nandina, Rosenfeld, Jill A., Sherlock, Mark, Syverson, Erin, White, Perrin C., Wise, Carol, Yu, Yao, Zacharin, Margaret, Banerjee, Indraneel, Reijns, Martin, Bober, Michael B., Semple, Robert K., Boulton, Simon J., Rios, Jonathan J., and Jackson, Andrew P.

Published
2018
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17. Linked-read genome sequencing identifies biallelic pathogenic variants in DONSON as a novel cause of Meier-Gorlin syndrome

Author

Knapp, Karen M, primary, Sullivan, Rosie, additional, Murray, Jennie, additional, Gimenez, Gregory, additional, Arn, Pamela, additional, D'Souza, Precilla, additional, Gezdirici, Alper, additional, Wilson, William G, additional, Jackson, Andrew P, additional, Ferreira, Carlos, additional, and Bicknell, Louise S, additional

Published
2019
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19. DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency

Author

Logan, Clare V., primary, Murray, Jennie E., additional, Parry, David A., additional, Robertson, Andrea, additional, Bellelli, Roberto, additional, Tarnauskaitė, Žygimantė, additional, Challis, Rachel, additional, Cleal, Louise, additional, Borel, Valerie, additional, Fluteau, Adeline, additional, Santoyo-Lopez, Javier, additional, Aitman, Tim, additional, Barroso, Inês, additional, Basel, Donald, additional, Bicknell, Louise S., additional, Goel, Himanshu, additional, Hu, Hao, additional, Huff, Chad, additional, Hutchison, Michele, additional, Joyce, Caroline, additional, Knox, Rachel, additional, Lacroix, Amy E., additional, Langlois, Sylvie, additional, McCandless, Shawn, additional, McCarrier, Julie, additional, Metcalfe, Kay A., additional, Morrissey, Rose, additional, Murphy, Nuala, additional, Netchine, Irène, additional, O’Connell, Susan M., additional, Olney, Ann Haskins, additional, Paria, Nandina, additional, Rosenfeld, Jill A., additional, Sherlock, Mark, additional, Syverson, Erin, additional, White, Perrin C., additional, Wise, Carol, additional, Yu, Yao, additional, Zacharin, Margaret, additional, Banerjee, Indraneel, additional, Reijns, Martin, additional, Bober, Michael B., additional, Semple, Robert K., additional, Boulton, Simon J., additional, Rios, Jonathan J., additional, Jackson, Andrew P., additional, Aitman, Timothy J., additional, Biankin, Andrew V., additional, Cooke, Susanna L., additional, Humphrey, Wendy Inglis, additional, Martin, Sancha, additional, Mennie, Lynne, additional, Meynert, Alison, additional, Miedzybrodzka, Zosia, additional, Murphy, Fiona, additional, Nourse, Craig, additional, Semple, Colin A., additional, and Williams, Nicola, additional

Published
2018
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20. Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

Author

Reynolds, John J., Bicknell, Louise S., Carroll, Paula, Higgs, Martin R., Shaheen, Ranad, Murray, Jennie E., Papadopoulos, Dimitrios K., Leitch, Andrea, Murina, Olga, Tarnauskaite, Zygimante, Wessel, Sarah R., Zlatanou, Anastasia, Vernet, Audrey, von Kriegsheim, Alex, Mottram, Rachel M. A., Logan, Clare V., Bye, Hannah, Li, Yun, Brean, Alexander, Maddirevula, Sateesh, Challis, Rachel C., Skouloudaki, Kassiani, Almoisheer, Agaadir, Alsaif, Hessa S., Amar, Ariella, Prescott, Natalie J., Bober, Michael B., Duker, Angela, Faqeih, Eissa, Seidahmed, Mohammed Zain, Al Tala, Saeed, Alswaid, Abdulrahman, Ahmed, Saleem, Al-Aama, Jumana Yousuf, Altmueller, Janine, Al Balwi, Mohammed, Brady, Angela F., Chessa, Luciana, Cox, Helen, Fischetto, Rita, Heller, Raoul, Henderson, Bertram D., Hobson, Emma, Nurnberg, Peter, Percin, E. Ferda, Peron, Angela, Spaccini, Luigina, Quigley, Alan J., Thakur, Seema, Wise, Carol A., Yoon, Grace, Alnemer, Maha, Tomancak, Pavel, Yigit, Goekhan, Taylor, A. Malcolm R., Reijns, Martin A. M., Simpson, Michael A., Cortez, David, Alkuraya, Fowzan S., Mathew, Christopher G., Jackson, Andrew P., Stewart, Grant S., Reynolds, John J., Bicknell, Louise S., Carroll, Paula, Higgs, Martin R., Shaheen, Ranad, Murray, Jennie E., Papadopoulos, Dimitrios K., Leitch, Andrea, Murina, Olga, Tarnauskaite, Zygimante, Wessel, Sarah R., Zlatanou, Anastasia, Vernet, Audrey, von Kriegsheim, Alex, Mottram, Rachel M. A., Logan, Clare V., Bye, Hannah, Li, Yun, Brean, Alexander, Maddirevula, Sateesh, Challis, Rachel C., Skouloudaki, Kassiani, Almoisheer, Agaadir, Alsaif, Hessa S., Amar, Ariella, Prescott, Natalie J., Bober, Michael B., Duker, Angela, Faqeih, Eissa, Seidahmed, Mohammed Zain, Al Tala, Saeed, Alswaid, Abdulrahman, Ahmed, Saleem, Al-Aama, Jumana Yousuf, Altmueller, Janine, Al Balwi, Mohammed, Brady, Angela F., Chessa, Luciana, Cox, Helen, Fischetto, Rita, Heller, Raoul, Henderson, Bertram D., Hobson, Emma, Nurnberg, Peter, Percin, E. Ferda, Peron, Angela, Spaccini, Luigina, Quigley, Alan J., Thakur, Seema, Wise, Carol A., Yoon, Grace, Alnemer, Maha, Tomancak, Pavel, Yigit, Goekhan, Taylor, A. Malcolm R., Reijns, Martin A. M., Simpson, Michael A., Cortez, David, Alkuraya, Fowzan S., Mathew, Christopher G., Jackson, Andrew P., and Stewart, Grant S.

Abstract

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

Published
2017

21. Linked-read genome sequencing identifies biallelic pathogenic variants in DONSONas a novel cause of Meier-Gorlin syndrome

Author

Knapp, Karen M, Sullivan, Rosie, Murray, Jennie, Gimenez, Gregory, Arn, Pamela, D'Souza, Precilla, Gezdirici, Alper, Wilson, William G, Jackson, Andrew P, Ferreira, Carlos, and Bicknell, Louise S

Abstract

MaterialLinked-read whole genome sequencing (WGS) presents a new opportunity for cost-efficient singleton sequencing in place of traditional trio-based designs while generating informative-phased variants, effective for recessive disorders when parental DNA is unavailable.MethodsWe have applied linked-read WGS to identify novel causes of Meier-Gorlin syndrome (MGORS), a condition recognised by short stature, microtia and patella hypo/aplasia. There are eight genes associated with MGORS to date, all encoding essential components involved in establishing and initiating DNA replication.ResultsOur successful phasing of linked-read data led to the identification of biallelic rare variants in four individuals (24% of our cohort) in DONSON, a recently established DNA replication fork surveillance factor. The variants include five novel missense and one deep intronic variant. All were demonstrated to be deleterious to function; the missense variants all disrupted the nuclear localisation of DONSON, while the intronic variant created a novel splice site that generated an out-of-frame transcript with no residual canonical transcript produced.ConclusionVariants in DONSONhave previously been associated with extreme microcephaly, short stature and limb anomalies and perinatal lethal microcephaly-micromelia syndrome. Our novel genetic findings extend the complicated spectrum of phenotypes associated with DONSONvariants and promote novel hypotheses for the role of DONSON in DNA replication. While our findings reiterate that MGORS is a disorder of DNA replication, the pathophysiology is obviously complex. This successful identification of a novel disease gene for MGORS highlights the utility of linked-read WGS as a successful technology to be considered in the genetic studies of recessive conditions.

Published
2020
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22. Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency

Author

Murray, Jennie E., Bicknell, Louise S., Yigit, Goekhan, Duker, Angela L., van Kogelenberg, Margriet, Haghayegh, Sara, Wieczorek, Dagmar, Kayserili, Huelya, Albert, Michael H., Wise, Carol A., Brandon, January, Kleefstra, Tjitske, Warris, Adilia, van der Flier, Michiel, Bamforth, J. Steven, Doonanco, Kurston, Ades, Lesley, Ma, Alan, Field, Michael, Johnson, Diana, Shackley, Fiona, Firth, Helen, Woods, C. Geoffrey, Nuernberg, Peter, Gatti, Richard A., Hurles, Matthew, Bober, Michael B., Wollnik, Bernd, Jackson, Andrew P., Murray, Jennie E., Bicknell, Louise S., Yigit, Goekhan, Duker, Angela L., van Kogelenberg, Margriet, Haghayegh, Sara, Wieczorek, Dagmar, Kayserili, Huelya, Albert, Michael H., Wise, Carol A., Brandon, January, Kleefstra, Tjitske, Warris, Adilia, van der Flier, Michiel, Bamforth, J. Steven, Doonanco, Kurston, Ades, Lesley, Ma, Alan, Field, Michael, Johnson, Diana, Shackley, Fiona, Firth, Helen, Woods, C. Geoffrey, Nuernberg, Peter, Gatti, Richard A., Hurles, Matthew, Bober, Michael B., Wollnik, Bernd, and Jackson, Andrew P.

Abstract

Ligase IV syndrome is a rare differential diagnosis for Nijmegen breakage syndrome owing to a shared predisposition to lympho-reticular malignancies, significant microcephaly, and radiation hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here, we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC -10.1 s.d., height -5.1 s.d.). Subsequently, most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognized immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype-phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency, and sometimes malignancy are long term sequelae of this disorder. Published 2013 Wiley Periodicals, Inc.

Published
2014

23. Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy

Author

Martin, Carol-Anne, Ahmad, Ilyas, Klingseisen, Anna, Hussain, Muhammad Sajid, Bicknell, Louise S., Leitch, Andrea, Nuernberg, Gudrun, Toliat, Mohammad Reza, Murray, Jennie E., Hunt, David, Khan, Fawad, Ali, Zafar, Tinschert, Sigrid, Ding, James, Keith, Charlotte, Harley, Margaret E., Heyn, Patricia, Mueller, Rolf, Hoffmann, Ingrid, Cormier-Daire, Valerie, Dollfus, Helene, Dupuis, Lucie, Bashamboo, Anu, McElreavey, Kenneth, Kariminejad, Ariana, Mendoza-Londono, Roberto, Moore, Anthony T., Saggar, Anand, Schlechter, Catie, Weleber, Richard, Thiele, Holger, Altmueller, Janine, Hoehne, Wolfgang, Hurles, Matthew E., Noegel, Angelika Anna, Baig, Shahid Mahmood, Nuernberg, Peter, Jackson, Andrew P., Martin, Carol-Anne, Ahmad, Ilyas, Klingseisen, Anna, Hussain, Muhammad Sajid, Bicknell, Louise S., Leitch, Andrea, Nuernberg, Gudrun, Toliat, Mohammad Reza, Murray, Jennie E., Hunt, David, Khan, Fawad, Ali, Zafar, Tinschert, Sigrid, Ding, James, Keith, Charlotte, Harley, Margaret E., Heyn, Patricia, Mueller, Rolf, Hoffmann, Ingrid, Cormier-Daire, Valerie, Dollfus, Helene, Dupuis, Lucie, Bashamboo, Anu, McElreavey, Kenneth, Kariminejad, Ariana, Mendoza-Londono, Roberto, Moore, Anthony T., Saggar, Anand, Schlechter, Catie, Weleber, Richard, Thiele, Holger, Altmueller, Janine, Hoehne, Wolfgang, Hurles, Matthew E., Noegel, Angelika Anna, Baig, Shahid Mahmood, Nuernberg, Peter, and Jackson, Andrew P.

Abstract

Centrioles are essential for ciliogenesis. However, mutations in centriole biogenesis genes have been reported in primary microcephaly and Seckel syndrome, disorders without the hallmark clinical features of ciliopathies. Here we identify mutations in the genes encoding PLK4 kinase, a master regulator of centriole duplication, and its substrate TUBGCP6 in individuals with microcephalic primordial dwarfism and additional congenital anomalies, including retinopathy, thereby extending the human phenotypic spectrum associated with centriole dysfunction. Furthermore, we establish that different levels of impaired PLK4 activity result in growth and cilia phenotypes, providing a mechanism by which microcephaly disorders can occur with or without ciliopathic features.

Published
2014

25. Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis.

Author

Martin, Carol-Anne, Murray, Jennie E., Carroll, Paula, Leitch, Andrea, Mackenzie, Karen J., Halachev, Mihail, Fetit, Ahmed E., Keith, Charlotte, Bicknell, Louise S., Fluteau, Adeline, Gautier, Philippe, Hall, Emma A., Joss, Shelagh, Soares, Gabriela, Silva, João, Bober, Michael B., Duker, Angela, Wise, Carol A., Quigley, Alan J., and Phadke, Shubha R.

Subjects
*CONDENSIN, *CHROMOSOMES, *MICROCEPHALY, *MITOSIS, *CHROMATIN, *DISEASE risk factors
Abstract

Compaction of chromosomes is essential for accurate segregation of the genome during mitosis. In vertebrates, two condensin complexes ensure timely chromosome condensation, sister chromatid disentanglement, and maintenance of mitotic chromosome structure. Here, we report that biallelic mutations in NCAPD2, NCAPH, or NCAPD3, encoding subunits of these complexes, cause microcephaly. In addition, hypomorphic Ncaph2 mice have significantly reduced brain size, with frequent anaphase chromatin bridge formation observed in apical neural progenitors during neurogenesis. Such DNA bridges also arise in condensin-deficient patient cells, where they are the consequence of failed sister chromatid disentanglement during chromosome compaction. This results in chromosome segregation errors, leading to micronucleus formation and increased aneuploidy in daughter cells. These findings establish "condensinopathies" as microcephalic disorders, with decatenation failure as an additional disease mechanism for microcephaly, implicating mitotic chromosome condensation as a key process ensuring mammalian cerebral cortex size. [ABSTRACT FROM AUTHOR]

Published
2016
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26. Should you keep pregnancy secret for 12 weeks?

Author

Jenni Murray; Jennie Agg

Abstract

THERE'S now something of a campaign to end what's known as the '12-week rule' - where a woman is expected to stay quiet about her pregnancy during the first trimester 'in case something goes wrong'. [ABSTRACT FROM PUBLISHER]

Published
2019

27. A syndromic form of Pierre Robin sequence is caused by 5q23 deletions encompassing FBN2 and PHAX

Author

Laura Mazzanti, Jacqueline K. Rainger, Felicity V. Mehendale, Morad Ansari, Antonio Percesepe, Jeanne Amiel, Helen V. Firth, Isabel M. Hanson, I. Karen Temple, Paola Ferrari, Koenraad Devriendt, David R. FitzPatrick, Alan Fryer, Jennie E. Murray, Christopher T. Gordon, Ansari, Morad, Rainger, Jacqueline K., Murray, Jennie E., Hanson, Isabel, Firth, Helen V., Mehendale, Felicity, Amiel, Jeanne, Gordon, Christopher T., Percesepe, Antonio, Mazzanti, Laura, Fryer, Alan, Ferrari, Paola, Devriendt, Koenraad, Temple, I. Karen, and Fitzpatrick, David R.

Subjects
Male, Candidate gene, Nucleocytoplasmic Transport Proteins, 5q deletion, Congenital contractural arachnodactyly, Fibrillin 2 (FBN2), Phosphorylated adaptor for RNA export (PHAX), Pierre Robin sequence, Talipes equinovarus, Fibrillin-2, Haploinsufficiency, Genome, Nucleocytoplasmic Transport Protein, Ear, External, Child, Genetics (clinical), Sequence Deletion, Genetics, 0303 health sciences, Robin Sequence, Pierre Robin Syndrome, Medicine (all), 030305 genetics & heredity, Microfilament Proteins, General Medicine, Syndrome, Phenotype, Talipes equinovaru, Cleft Palate, Clubfoot, Phosphoprotein, Pierre Robin syndrome, Chromosomes, Human, Pair 5, Female, Human, Contracture, Adolescent, Mutation, Missense, Biology, Fibrillins, Fingers, 03 medical and health sciences, Young Adult, Genetic, Finger, medicine, Humans, Gene, 030304 developmental biology, Microfilament Protein, medicine.disease, Phosphoproteins, Gene Deletion
Abstract

Pierre Robin sequence (PRS) is an aetiologically distinct subgroup of cleft palate. We aimed to define the critical genomic interval from five different 5q22-5q31 deletions associated with PRS or PRS-associated features and assess each gene within the region as a candidate for the PRS component of the phenotype. Clinical array-based comparative genome hybridisation (aCGH) data were used to define a 2.08 Mb minimum region of overlap among four de novo deletions and one mother-son inherited deletion associated with at least one component of PRS. Commonly associated anomalies were talipes equinovarus (TEV), finger contractures and crumpled ear helices. Expression analysis of the orthologous genes within the PRS critical region in embryonic mice showed that the strongest candidate genes were FBN2 and PHAX. Targeted aCGH of the critical region and sequencing of these genes in a cohort of 25 PRS patients revealed no plausible disease-causing mutations. In conclusion, deletion of ?2 Mb on 5q23 region causes a clinically recognisable subtype of PRS. Haploinsufficiency for FBN2 accounts for the digital and auricular features. A possible critical region for TEV is distinct and telomeric to the PRS region. The molecular basis of PRS in these cases remains undetermined but haploinsufficiency for PHAX is a plausible mechanism.

Published
2014

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