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148 results on '"Trevor Cole"'

1. Carpal tunnel syndrome in paediatric patients: A novel association with Kosaki overgrowth syndrome

Author: Harriet Walker, Alison Foster, Trevor Cole, and Andrea Jester
Subjects: Kosaki overgrowth syndrome, KOGS, Carpal tunnel syndrome, Paediatric carpal tunnel syndrome, Surgery, RD1-811
Abstract: Summary: Carpal tunnel syndrome in a paediatric population is vanishingly rare and usually associated with lysosomal storage disorders such as mucopolysaccharidosis (MPS). Overgrowth syndromes similarly are rare and are characterised by increased skeletal growth alongside typical dysmorphic features and intellectual delay and as such the acronym OGID (overgrowth intellectual delay) is now widely used. Kosaki overgrowth syndrome (KOGS) is a newly recognised OGID with only 6 cases to date reported in the literature. Here we report a 7th case of KOGS with a new finding of carpal tunnel syndrome not previously described. We discuss similarities between the intraoperative findings during carpal tunnel decompression with findings seen in patients with MPS.
Published: 2020
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2. The evolving therapeutic landscape of genetic skeletal disorders

Author: Ataf Hussain Sabir and Trevor Cole
Subjects: Skeletal, Bone, Dysplasia, Rare, Genetic, Hereditary, Medicine
Abstract: Abstract Background Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment technologies however, are leading to unparalleled therapeutic advance. This review explores the evolving therapeutic landscape of genetic skeletal disorders (GSDs); the key conditions and there key differentials. Methods A retrospective literature based review was conducted in December 2018 using a systematic search strategy for relevant articles and trials in Pubmed and clinicaltrials.gov respectively. Over 140 articles and 80 trials were generated for review. Results Over 20 personalised therapies are discussed in addition to several novel disease modifying treatments in over 25 GSDs. Treatments discussed are at different stages from preclinical studies to clinical trials and approved drugs, including; Burosumab for X-linked hypophosphatemia, Palovarotene for Hereditary Multiple Exostoses, Carbamazepine for Metaphyseal Chondrodysplasia (Schmid type), Lithium carbonate and anti-sclerostin therapy for Osteoporosis Pseudoglioma syndrome and novel therapies for Osteopetrosis. We also discuss therapeutic advances in Achondroplasia, Osteogenesis Imperfecta (OI), Hypophosphotasia (HPP), Fibrodysplasia Ossificans Progressiva, and RNA silencing therapies in preclinical studies for OI and HPP. Discussion It is an exciting time for GSD therapies despite the challenges of drug development in rare diseases. In discussing emerging therapies, we explore novel approaches to drug development from drug repurposing to in-utero stem cell transplants. We highlight the improved understanding of bone pathophysiology, genetic pathways and challenges of developing gene therapies for GSDs.
Published: 2019
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3. Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing

Author: Alba Sanchis-Juan, Jonathan Stephens, Courtney E. French, Nicholas Gleadall, Karyn Mégy, Christopher Penkett, Olga Shamardina, Kathleen Stirrups, Isabelle Delon, Eleanor Dewhurst, Helen Dolling, Marie Erwood, Detelina Grozeva, Luca Stefanucci, Gavin Arno, Andrew R. Webster, Trevor Cole, Topun Austin, Ricardo Garcia Branco, Willem H. Ouwehand, F. Lucy Raymond, and Keren J. Carss
Subjects: Genome sequencing, Next-generation sequencing, Complex structural variant, Nanopore, ARID1B, HNRNPU, Medicine, Genetics, QH426-470
Abstract: Abstract Background Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation. Methods We performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case. Results We identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements. Conclusions Our results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation.
Published: 2018
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4. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

Author: Ana Osorio, Roger L Milne, Karoline Kuchenbaecker, Tereza Vaclová, Guillermo Pita, Rosario Alonso, Paolo Peterlongo, Ignacio Blanco, Miguel de la Hoya, Mercedes Duran, Orland Díez, Teresa Ramón Y Cajal, Irene Konstantopoulou, Cristina Martínez-Bouzas, Raquel Andrés Conejero, Penny Soucy, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, SWE-BRCA, Brita Arver, Johanna Rantala, Niklas Loman, Hans Ehrencrona, Olufunmilayo I Olopade, Mary S Beattie, Susan M Domchek, Katherine Nathanson, Timothy R Rebbeck, Banu K Arun, Beth Y Karlan, Christine Walsh, Jenny Lester, Esther M John, Alice S Whittemore, Mary B Daly, Melissa Southey, John Hopper, Mary B Terry, Saundra S Buys, Ramunas Janavicius, Cecilia M Dorfling, Elizabeth J van Rensburg, Linda Steele, Susan L Neuhausen, Yuan Chun Ding, Thomas V O Hansen, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Mar Infante, Belén Herráez, Leticia Thais Moreno, Jeffrey N Weitzel, Josef Herzog, Kisa Weeman, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Giulietta Scuvera, Bernardo Bonanni, Frederique Mariette, Sara Volorio, Alessandra Viel, Liliana Varesco, Laura Papi, Laura Ottini, Maria Grazia Tibiletti, Paolo Radice, Drakoulis Yannoukakos, Judy Garber, Steve Ellis, Debra Frost, Radka Platte, Elena Fineberg, Gareth Evans, Fiona Lalloo, Louise Izatt, Ros Eeles, Julian Adlard, Rosemarie Davidson, Trevor Cole, Diana Eccles, Jackie Cook, Shirley Hodgson, Carole Brewer, Marc Tischkowitz, Fiona Douglas, Mary Porteous, Lucy Side, Lisa Walker, Patrick Morrison, Alan Donaldson, John Kennedy, Claire Foo, Andrew K Godwin, Rita Katharina Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hans Jörg Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Andrea Gehrig, Dominique Stoppa-Lyonnet, Olga M Sinilnikova, Sylvie Mazoyer, Francesca Damiola, Bruce Poppe, Kathleen Claes, Marion Piedmonte, Kathy Tucker, Floor Backes, Gustavo Rodríguez, Wendy Brewster, Katie Wakeley, Thomas Rutherford, Trinidad Caldés, Heli Nevanlinna, Kristiina Aittomäki, Matti A Rookus, Theo A M van Os, Lizet van der Kolk, J L de Lange, Hanne E J Meijers-Heijboer, A H van der Hout, Christi J van Asperen, Encarna B Gómez Garcia, Nicoline Hoogerbrugge, J Margriet Collée, Carolien H M van Deurzen, Rob B van der Luijt, Peter Devilee, HEBON, Edith Olah, Conxi Lázaro, Alex Teulé, Mireia Menéndez, Anna Jakubowska, Cezary Cybulski, Jacek Gronwald, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Oskar Th Johannsson, Christine Maugard, Marco Montagna, Silvia Tognazzo, Manuel R Teixeira, Sue Healey, KConFab Investigators, Curtis Olswold, Lucia Guidugli, Noralane Lindor, Susan Slager, Csilla I Szabo, Joseph Vijai, Mark Robson, Noah Kauff, Liying Zhang, Rohini Rau-Murthy, Anneliese Fink-Retter, Christian F Singer, Christine Rappaport, Daphne Geschwantler Kaulich, Georg Pfeiler, Muy-Kheng Tea, Andreas Berger, Catherine M Phelan, Mark H Greene, Phuong L Mai, Flavio Lejbkowicz, Irene Andrulis, Anna Marie Mulligan, Gord Glendon, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Lone Sunde, Mads Thomassen, Torben A Kruse, Uffe Birk Jensen, Eitan Friedman, Yael Laitman, Shani Paluch Shimon, Jacques Simard, Douglas F Easton, Kenneth Offit, Fergus J Couch, Georgia Chenevix-Trench, Antonis C Antoniou, and Javier Benitez
Subjects: Genetics, QH426-470
Abstract: Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p
Published: 2014
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5. Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype–phenotype correlation study

Author: Lucy Loong, Agostina Tardivo, Alexej Knaus, Mona Hashim, Alistair T. Pagnamenta, Kerstin Alt, Helena Böhrer-Rabel, Alfonso Caro-Llopis, Trevor Cole, Felix Distelmaier, Patrick Edery, Carlos R. Ferreira, Aleksandra Jezela-Stanek, Bronwyn Kerr, Gerhard Kluger, Peter M. Krawitz, Marius Kuhn, Johannes R. Lemke, Gaetan Lesca, Sally Ann Lynch, Francisco Martinez, Caroline Maxton, Hanna Mierzewska, Sandra Monfort, Joost Nicolai, Carmen Orellana, Deb K. Pal, Rafał Płoski, Oliver W. Quarrell, Monica Rosello, Małgorzata Rydzanicz, Ataf Sabir, Robert Śmigiel, Alexander P.A. Stegmann, Helen Stewart, Constance Stumpel, Elżbieta Szczepanik, Andreas Tzschach, Lynne Wolfe, Jenny C. Taylor, Yoshiko Murakami, Taroh Kinoshita, Allan Bayat, Usha Kini, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: DA KG Lab Specialisten (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), and Klinische Genetica
Subjects: Genetics (clinical)
Abstract: PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.
Published: 2023

6. Identifying phenotypic expansions for congenital diaphragmatic hernia plus ( <scp>CDH</scp> +) using <scp>DECIPHER</scp> data

Author: Amy Hardcastle, Aliska M. Berry, Ian M. Campbell, Xiaonan Zhao, Pengfei Liu, Amanda E. Gerard, Jill A. Rosenfeld, Saumya D. Sisoudiya, Andres Hernandez‐Garcia, Sara Loddo, Silvia Di Tommaso, Antonio Novelli, Maria L. Dentici, Rossella Capolino, Maria C. Digilio, Ludovico Graziani, Cecilie F. Rustad, Katherine Neas, Giovanni B. Ferrero, Alfredo Brusco, Eleonora Di Gregorio, Diana Wellesley, Claire Beneteau, Madeleine Joubert, Kris Van Den Bogaert, Anneleen Boogaerts, Dominic J. McMullan, John Dean, Maria G. Giuffrida, Laura Bernardini, Vinod Varghese, Nora L. Shannon, Rachel E. Harrison, Wayne W. K. Lam, Shane McKee, Peter D. Turnpenny, Trevor Cole, Jenny Morton, Jacqueline Eason, Marilyn C. Jones, Rebecca Hall, Michael Wright, Karen Horridge, Chad A. Shaw, Wendy K. Chung, and Daryl A. Scott
Subjects: DNA Copy Number Variations, Diaphragm, USP9X, CREBBP, DECIPHER database, SMARCA4, UBA2, congenital diaphragmatic hernia, Mice, Genetics, Animals, Hernias, Diaphragmatic, Congenital, Genetics (clinical)
Abstract: Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development.
Published: 2022

7. Risk Factors for Primary Bone Cancer After Childhood Cancer: A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study

Author: Raoul C. Reulen, David L. Winter, Ibrahim Diallo, Cristina Veres, Damien Llanas, Rodrigue S. Allodji, Francesca Bagnasco, Edit Bárdi, Elizabeth A.M. Feijen, Daniela Alessi, Miranda M. Fidler-Benaoudia, Stine Høgsholt, Jop C. Teepen, Helena Linge, Nadia Haddy, Julianne Byrne, Ghazi Debiche, Desiree Grabow, Thorgerdur Gudmundsdottir, Romain Fauchery, Wael Zrafi, Gisela Michel, Hilde Øfstaas, Peter Kaatsch, Giao Vu-Bezin, Helen Jenkinson, Melanie Kaiser, Roderick Skinner, Trevor Cole, Nicolas Waespe, Grit Sommer, Susanne Nordenfelt, Momcilo Jankovic, Tuomas Lähteenmäki Taalas, Milena M. Maule, Helena J.H. van der Pal, Cécile M. Ronckers, Flora E. van Leeuwen, Judith L. Kok, Monica Terenziani, Maria Winther Gunnes, Thomas Wiebe, Carlotta Sacerdote, Zsuzsanna Jakab, Riccardo Haupt, Päivi M. Lähteenmäki, Lorna Zadravec Zaletel, Claudia E. Kuehni, Jeanette Falck Winther, Leontien C.M. Kremer, Lars Hjorth, Florent de Vathaire, and Michael M. Hawkins
Subjects: Cancer Research, Oncology
Abstract: PURPOSE Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy. METHODS Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship. RESULTS The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation ( Ptrend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer. CONCLUSION To our knowledge, we demonstrate—for the first time—that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.
Published: 2023

8. Supplementary Table 2 from Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Eitan Friedman, Antonis C. Antoniou, Georgia Chenevix-Trench, Paul D.P. Pharoah, Andrew Lee, Sue Healey, Daniel Barrowdale, Lesley McGuffog, Karoline B. Kuchenbaecker, Åke Borg, Marie Stenmark Askmalm, Hans Ehrencrona, Anna von Wachenfeldt, Johanna Rantala, Yael Laitman, Uffe Birk Jensen, Mads Thomassen, Inge Sokilde Pedersen, Anders Bojesen, Amanda Ewart Toland, Irene L. Andrulis, Sandrine Tchatchou, Gord Glendon, Anna Marie Mulligan, Gad Rennert, Phuong L. Mai, Mark H. Greene, Catherine M. Phelan, Muy-Kheng M. Tea, Georg Pfeiler, Daphne Geschwantler Kaulich, Christine Rappaport, Christian F. Singer, Andreas Berger, Vijai Joseph, Liying Zhang, Mark E. Robson, Lauren Jacobs, Marina Corines, Kenneth Offit, Csilla I. Szabo, Xianshu Wang, Noralane M. Lindor, Fergus J. Couch, Curtis Olswold, Manuel R. Teixeira, Jocelyne Chiquette, Adalgeir Arason, Grzegorz Sukiennicki, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Jacek Gronwald, Cezary Cybulski, Lidia Feliubadalo, Joan Brunet, Conxi Lazaro, Ignacio Blanco, Orland Diez, Edith Olah, J. Margriet Collée, Helena C. van Doorn, Margreet G.E.M. Ausems, Nicoline Hoogerbrugge, Maaike P.G. Vreeswijk, Annemarie H. van der Hout, Hanne E.J. Meijers-Heijboer, Theo A.M. van Os, Kristiina Aittomäki, Heli Nevanlinna, Pedro Perez Segura, Miguel de la Hoya, Larry J. Copeland, Gustavo C. Rodriguez, Michael L. Friedlander, Marion Piedmonte, Muriel Belotti, Sylvie Mazoyer, Pascal Pujol, Olivier Caron, Olga M. Sinilnikova, Nadia Boutry-Kryza, Lisa Golmard, Laurence Venat-Bouvet, Laure Barjhoux, Isabelle Coupier, Francesca Damiola, Dominique Stoppa-Lyonnet, Claude Houdayer, Capucine Delnatte, Bruno Buecher, Brigitte Bressac-de Paillerets, Shan Wang-Gohrke, Barbara Wappenschmidt, Raymonda Varon-Mateeva, Norbert Arnold, Nina Ditsch, Kerstin Rhiem, Karin Kast, Hansjoerg Plendl, Doris Steinemann, Dieter Niederacher, Christoph Engel, Christian Sutter, Andrea Gehrig, Alfons Meindl, Tom Van Maerken, Kathleen Claes, Andrew K. Godwin, Trevor Cole, Steve Ellis, Shirley V. Hodgson, Rosemarie Davidson, Radka Platte, Patrick J. Morrison, Mary E. Porteous, Mark T. Rogers, M. John Kennedy, Lucy E. Side, Louise Izatt, Lisa Walker, Julian Barwell, Julian Adlard, Marc Tischkowitz, Jackie Cook, Angela Brady, Diana Eccles, Debra Frost, D. Gareth R. Evans, Claire Foo, Carole Brewer, Alan Donaldson, Judy E. Garber, Florentia Fostira, Athanassios Vratimos, Paolo Radice, Maria Grazia Tibiletti, Aline Martayan, Laura Papi, Giuseppe Giannini, Alessandra Viel, Stefano Fortuzzi, Frederique Mariette, Filomena Ficarazzi, Monica Barile, Giulietta Scuvera, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Jeffrey N. Weitzel, Kathleen R. Blazer, Edye E. Conway, Javier Benitez, Cristina Martínez-Bouzas, Ana Osorio, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Thomas V.O. Hansen, Susan L. Neuhausen, Yuan Chun Ding, Elizabeth J. van Rensburg, Cecilia M. Dorfling, Ramunas Janavicius, Saundra S. Buys, David E. Goldgar, Melissa C. Southey, Alex Miron, Wendy K. Chung, Jenny Lester, Sandra Orsulic, Beth Y. Karlan, Banu K. Arun, Timothy R. Rebbeck, Susan M. Domchek, Katherine L. Nathanson, Robert L. Nussbaum, Olufunmilayo I. Olopade, Encarna B. Gómez Garcia, Anna Jakubowska, Jan Lubinski, Laura Matricardi, Marco Montagna, Ana-Teresa Maia, Felicity Lose, Logan C. Walker, Amanda B. Spurdle, Frederieke H. van der Baan, Marjanka K. Schmidt, Matti A. Rookus, Bowang Chen, Stefan Wilkening, Ute Hamann, Douglas F. Easton, Rosalind A. Eeles, Penny Soucy, Jacques Simard, Rita K. Schmutzler, Anja Rudolph, Kirsten B. Moysich, Jenny Chang-Claude, and Paolo Peterlongo
Abstract: Supplementary Table 2. Results of the statistical analyses in BRCA mutation carriers.
Published: 2023

9. Supplementary Table 1 from Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Eitan Friedman, Antonis C. Antoniou, Georgia Chenevix-Trench, Paul D.P. Pharoah, Andrew Lee, Sue Healey, Daniel Barrowdale, Lesley McGuffog, Karoline B. Kuchenbaecker, Åke Borg, Marie Stenmark Askmalm, Hans Ehrencrona, Anna von Wachenfeldt, Johanna Rantala, Yael Laitman, Uffe Birk Jensen, Mads Thomassen, Inge Sokilde Pedersen, Anders Bojesen, Amanda Ewart Toland, Irene L. Andrulis, Sandrine Tchatchou, Gord Glendon, Anna Marie Mulligan, Gad Rennert, Phuong L. Mai, Mark H. Greene, Catherine M. Phelan, Muy-Kheng M. Tea, Georg Pfeiler, Daphne Geschwantler Kaulich, Christine Rappaport, Christian F. Singer, Andreas Berger, Vijai Joseph, Liying Zhang, Mark E. Robson, Lauren Jacobs, Marina Corines, Kenneth Offit, Csilla I. Szabo, Xianshu Wang, Noralane M. Lindor, Fergus J. Couch, Curtis Olswold, Manuel R. Teixeira, Jocelyne Chiquette, Adalgeir Arason, Grzegorz Sukiennicki, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Jacek Gronwald, Cezary Cybulski, Lidia Feliubadalo, Joan Brunet, Conxi Lazaro, Ignacio Blanco, Orland Diez, Edith Olah, J. Margriet Collée, Helena C. van Doorn, Margreet G.E.M. Ausems, Nicoline Hoogerbrugge, Maaike P.G. Vreeswijk, Annemarie H. van der Hout, Hanne E.J. Meijers-Heijboer, Theo A.M. van Os, Kristiina Aittomäki, Heli Nevanlinna, Pedro Perez Segura, Miguel de la Hoya, Larry J. Copeland, Gustavo C. Rodriguez, Michael L. Friedlander, Marion Piedmonte, Muriel Belotti, Sylvie Mazoyer, Pascal Pujol, Olivier Caron, Olga M. Sinilnikova, Nadia Boutry-Kryza, Lisa Golmard, Laurence Venat-Bouvet, Laure Barjhoux, Isabelle Coupier, Francesca Damiola, Dominique Stoppa-Lyonnet, Claude Houdayer, Capucine Delnatte, Bruno Buecher, Brigitte Bressac-de Paillerets, Shan Wang-Gohrke, Barbara Wappenschmidt, Raymonda Varon-Mateeva, Norbert Arnold, Nina Ditsch, Kerstin Rhiem, Karin Kast, Hansjoerg Plendl, Doris Steinemann, Dieter Niederacher, Christoph Engel, Christian Sutter, Andrea Gehrig, Alfons Meindl, Tom Van Maerken, Kathleen Claes, Andrew K. Godwin, Trevor Cole, Steve Ellis, Shirley V. Hodgson, Rosemarie Davidson, Radka Platte, Patrick J. Morrison, Mary E. Porteous, Mark T. Rogers, M. John Kennedy, Lucy E. Side, Louise Izatt, Lisa Walker, Julian Barwell, Julian Adlard, Marc Tischkowitz, Jackie Cook, Angela Brady, Diana Eccles, Debra Frost, D. Gareth R. Evans, Claire Foo, Carole Brewer, Alan Donaldson, Judy E. Garber, Florentia Fostira, Athanassios Vratimos, Paolo Radice, Maria Grazia Tibiletti, Aline Martayan, Laura Papi, Giuseppe Giannini, Alessandra Viel, Stefano Fortuzzi, Frederique Mariette, Filomena Ficarazzi, Monica Barile, Giulietta Scuvera, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Jeffrey N. Weitzel, Kathleen R. Blazer, Edye E. Conway, Javier Benitez, Cristina Martínez-Bouzas, Ana Osorio, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Thomas V.O. Hansen, Susan L. Neuhausen, Yuan Chun Ding, Elizabeth J. van Rensburg, Cecilia M. Dorfling, Ramunas Janavicius, Saundra S. Buys, David E. Goldgar, Melissa C. Southey, Alex Miron, Wendy K. Chung, Jenny Lester, Sandra Orsulic, Beth Y. Karlan, Banu K. Arun, Timothy R. Rebbeck, Susan M. Domchek, Katherine L. Nathanson, Robert L. Nussbaum, Olufunmilayo I. Olopade, Encarna B. Gómez Garcia, Anna Jakubowska, Jan Lubinski, Laura Matricardi, Marco Montagna, Ana-Teresa Maia, Felicity Lose, Logan C. Walker, Amanda B. Spurdle, Frederieke H. van der Baan, Marjanka K. Schmidt, Matti A. Rookus, Bowang Chen, Stefan Wilkening, Ute Hamann, Douglas F. Easton, Rosalind A. Eeles, Penny Soucy, Jacques Simard, Rita K. Schmutzler, Anja Rudolph, Kirsten B. Moysich, Jenny Chang-Claude, and Paolo Peterlongo
Abstract: Supplementary Table 1. The 3,248 SNPs included in the study
Published: 2023

10. Supplementary Tables 1-4 from Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Jacques Simard, Kenneth Offit, Georgia Chenevix-Trench, Douglas F. Easton, Phuong L. Mai, Mark H. Greene, Paolo Radice, Liliana Varesco, Giuseppe Giannini, Alessandra Viel, Loris Bernard, Monica Barile, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Paolo Peterlongo, V. Shane Pankratz, Zachary Fredericksen, Noralane M. Lindor, Yuan Chun Ding, Susan L. Neuhausen, Amanda B. Spurdle, Marc D. Tischkowitz, Heli Nevanlinna, Taru A. Muranen, Miguel de la Hoya, Trinidad Caldes, Wolfram Heinritz, Britta Fiebig, Karin Kast, Christian Sutter, Andrea Gehrig, Helmut Deissler, Raymonda Varon-Mateeva, Dorothea Gadzicki, Sabine Preisler-Adams, Dieter Niederacher, Simone Heidemann, Norbert Arnold, Nina Ditsch, Alfons Meindl, Christoph Engel, Barbara Wappenschmidt, Rita K. Schmutzler, Ava Kwong, Orland Diez, Cecelia M. Dorfling, Elizabeth J. van Rensburg, Mary S. Beattie, Patricia A. Ganz, Soo Hwang Teo, Edith Olah, Christine S. Walsh, Beth Y. Karlan, Kunle O. Odunsi, Paul P.D. Pharoah, Simon A. Gayther, Joan Brunet, Lidia Feliubadalo, Ignacio Blanco, Conxi Lazaro, Ramunas Janavicius, Claudine Isaacs, Evgeny N. Imyanitov, Simona Agata, Marco Montagna, Amanda Ewart-Toland, Katie Wakeley, John Boggess, Wendy S. Rubinstein, Jack Basil, Kelly Phillips, Marion Piedmonte, Mark E. Robson, Kara Sarrel, Sohela Shah, Joseph Vijai, Aðalgeir Arason, Finn C. Nielsen, Thomas V.O. Hansen, Anneliese Fink-Retter, Muy-Kheng M. Tea, Christine Rappaport, Christian F. Singer, David E. Goldgar, John L. Hopper, Melissa C. Southey, Alexander Miron, Esther M. John, Wendy K. Chung, MaryBeth Terry, Mary B. Daly, Saundra S. Buys, Carrie L. Snyder, Henry T. Lynch, Linda Akloul, Capucine Delnatte, Isabelle Coupier, Pascal Pujol, Olivier Caron, Brigitte Bressac-de Paillerets, Nadia Boutry-Kryza, Mélanie Léoné, Sylvie Mazoyer, François Cornelis, Laurent Castera, Marion Fassy-Colcombet, Dominique Stoppa-Lyonnet, Andrew K. Godwin, Betsy Bove, Lucy E. Side, M. John Kennedy, Mary E. Porteous, Lisa Walker, Patrick J. Morrison, Shirley V. Hodgson, Fiona Douglas, Carole Brewer, Joan Paterson, Jackie Cook, Trevor Cole, Diana M. Eccles, Rosemarie Davidson, Julian Adlard, Rosalind A. Eeles, Chris Jacobs, D. Gareth Evans, Elena Fineberg, Radka Platte, Steve D. Ellis, Debra Frost, Susan Peock, Margreet G.E.M. Ausems, Rogier A. Oldenburg, Maartje J. Hooning, Marleen Kets, Marinus J. Blok, Juul Wijnen, Hanne E.J. Meijers-Heijboer, Flora E. van Leeuwen, Theo A. van Os, Frans B.L. Hogervorst, Ute Hamann, Javier Benitez, María Isabel Tejada, Mercedes Durán, Ana Osorio, Bohdan Górski, Cezary Cybulski, Jacek Gronwald, Tomasz Byrski, Tomasz Huzarski, Elżbieta Złowocka, Katarzyna Durda, Katarzyna Jaworska, Jan Lubinski, Ania Jakubowska, Susan M. Domchek, Timothy R. Rebbeck, Katherine L. Nathanson, Per Karlsson, Hans Ehrencrona, Maria Soller, Niklas Loman, Gisela Barbany-Bustinza, Anna von Wachenfeldt, Maria A. Caligo, Torben A. Kruse, Anne-Bine Skytte, Uffe Birk Jensen, Anne-Marie Gerdes, Mads Thomassen, Anna Marie Mulligan, Hilmi Ozcelik, Irene L. Andrulis, Olga M. Sinilnikova, Sue Healey, Andrew Lee, Daniel Barrowdale, Lesley McGuffog, Tomas Kirchhoff, Xianshu Wang, Xiaoqing Chen, Jonathan Beesley, Penny Soucy, Karoline B. Kuchenbaecker, Susan J. Ramus, Antonis C. Antoniou, Mia M. Gaudet, and Fergus J. Couch
Abstract: PDF file - 90K
Published: 2023

11. Data from Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Jacques Simard, Kenneth Offit, Georgia Chenevix-Trench, Douglas F. Easton, Phuong L. Mai, Mark H. Greene, Paolo Radice, Liliana Varesco, Giuseppe Giannini, Alessandra Viel, Loris Bernard, Monica Barile, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Paolo Peterlongo, V. Shane Pankratz, Zachary Fredericksen, Noralane M. Lindor, Yuan Chun Ding, Susan L. Neuhausen, Amanda B. Spurdle, Marc D. Tischkowitz, Heli Nevanlinna, Taru A. Muranen, Miguel de la Hoya, Trinidad Caldes, Wolfram Heinritz, Britta Fiebig, Karin Kast, Christian Sutter, Andrea Gehrig, Helmut Deissler, Raymonda Varon-Mateeva, Dorothea Gadzicki, Sabine Preisler-Adams, Dieter Niederacher, Simone Heidemann, Norbert Arnold, Nina Ditsch, Alfons Meindl, Christoph Engel, Barbara Wappenschmidt, Rita K. Schmutzler, Ava Kwong, Orland Diez, Cecelia M. Dorfling, Elizabeth J. van Rensburg, Mary S. Beattie, Patricia A. Ganz, Soo Hwang Teo, Edith Olah, Christine S. Walsh, Beth Y. Karlan, Kunle O. Odunsi, Paul P.D. Pharoah, Simon A. Gayther, Joan Brunet, Lidia Feliubadalo, Ignacio Blanco, Conxi Lazaro, Ramunas Janavicius, Claudine Isaacs, Evgeny N. Imyanitov, Simona Agata, Marco Montagna, Amanda Ewart-Toland, Katie Wakeley, John Boggess, Wendy S. Rubinstein, Jack Basil, Kelly Phillips, Marion Piedmonte, Mark E. Robson, Kara Sarrel, Sohela Shah, Joseph Vijai, Aðalgeir Arason, Finn C. Nielsen, Thomas V.O. Hansen, Anneliese Fink-Retter, Muy-Kheng M. Tea, Christine Rappaport, Christian F. Singer, David E. Goldgar, John L. Hopper, Melissa C. Southey, Alexander Miron, Esther M. John, Wendy K. Chung, MaryBeth Terry, Mary B. Daly, Saundra S. Buys, Carrie L. Snyder, Henry T. Lynch, Linda Akloul, Capucine Delnatte, Isabelle Coupier, Pascal Pujol, Olivier Caron, Brigitte Bressac-de Paillerets, Nadia Boutry-Kryza, Mélanie Léoné, Sylvie Mazoyer, François Cornelis, Laurent Castera, Marion Fassy-Colcombet, Dominique Stoppa-Lyonnet, Andrew K. Godwin, Betsy Bove, Lucy E. Side, M. John Kennedy, Mary E. Porteous, Lisa Walker, Patrick J. Morrison, Shirley V. Hodgson, Fiona Douglas, Carole Brewer, Joan Paterson, Jackie Cook, Trevor Cole, Diana M. Eccles, Rosemarie Davidson, Julian Adlard, Rosalind A. Eeles, Chris Jacobs, D. Gareth Evans, Elena Fineberg, Radka Platte, Steve D. Ellis, Debra Frost, Susan Peock, Margreet G.E.M. Ausems, Rogier A. Oldenburg, Maartje J. Hooning, Marleen Kets, Marinus J. Blok, Juul Wijnen, Hanne E.J. Meijers-Heijboer, Flora E. van Leeuwen, Theo A. van Os, Frans B.L. Hogervorst, Ute Hamann, Javier Benitez, María Isabel Tejada, Mercedes Durán, Ana Osorio, Bohdan Górski, Cezary Cybulski, Jacek Gronwald, Tomasz Byrski, Tomasz Huzarski, Elżbieta Złowocka, Katarzyna Durda, Katarzyna Jaworska, Jan Lubinski, Ania Jakubowska, Susan M. Domchek, Timothy R. Rebbeck, Katherine L. Nathanson, Per Karlsson, Hans Ehrencrona, Maria Soller, Niklas Loman, Gisela Barbany-Bustinza, Anna von Wachenfeldt, Maria A. Caligo, Torben A. Kruse, Anne-Bine Skytte, Uffe Birk Jensen, Anne-Marie Gerdes, Mads Thomassen, Anna Marie Mulligan, Hilmi Ozcelik, Irene L. Andrulis, Olga M. Sinilnikova, Sue Healey, Andrew Lee, Daniel Barrowdale, Lesley McGuffog, Tomas Kirchhoff, Xianshu Wang, Xiaoqing Chen, Jonathan Beesley, Penny Soucy, Karoline B. Kuchenbaecker, Susan J. Ramus, Antonis C. Antoniou, Mia M. Gaudet, and Fergus J. Couch
Abstract: Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; P = 7.42 × 10−4] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73–0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05–1.29; P = 3.8 × 10−4) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; P = 1.8 × 10−3).Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR.
Published: 2023

12. Supplementary Table 3 from Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Eitan Friedman, Antonis C. Antoniou, Georgia Chenevix-Trench, Paul D.P. Pharoah, Andrew Lee, Sue Healey, Daniel Barrowdale, Lesley McGuffog, Karoline B. Kuchenbaecker, Åke Borg, Marie Stenmark Askmalm, Hans Ehrencrona, Anna von Wachenfeldt, Johanna Rantala, Yael Laitman, Uffe Birk Jensen, Mads Thomassen, Inge Sokilde Pedersen, Anders Bojesen, Amanda Ewart Toland, Irene L. Andrulis, Sandrine Tchatchou, Gord Glendon, Anna Marie Mulligan, Gad Rennert, Phuong L. Mai, Mark H. Greene, Catherine M. Phelan, Muy-Kheng M. Tea, Georg Pfeiler, Daphne Geschwantler Kaulich, Christine Rappaport, Christian F. Singer, Andreas Berger, Vijai Joseph, Liying Zhang, Mark E. Robson, Lauren Jacobs, Marina Corines, Kenneth Offit, Csilla I. Szabo, Xianshu Wang, Noralane M. Lindor, Fergus J. Couch, Curtis Olswold, Manuel R. Teixeira, Jocelyne Chiquette, Adalgeir Arason, Grzegorz Sukiennicki, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Jacek Gronwald, Cezary Cybulski, Lidia Feliubadalo, Joan Brunet, Conxi Lazaro, Ignacio Blanco, Orland Diez, Edith Olah, J. Margriet Collée, Helena C. van Doorn, Margreet G.E.M. Ausems, Nicoline Hoogerbrugge, Maaike P.G. Vreeswijk, Annemarie H. van der Hout, Hanne E.J. Meijers-Heijboer, Theo A.M. van Os, Kristiina Aittomäki, Heli Nevanlinna, Pedro Perez Segura, Miguel de la Hoya, Larry J. Copeland, Gustavo C. Rodriguez, Michael L. Friedlander, Marion Piedmonte, Muriel Belotti, Sylvie Mazoyer, Pascal Pujol, Olivier Caron, Olga M. Sinilnikova, Nadia Boutry-Kryza, Lisa Golmard, Laurence Venat-Bouvet, Laure Barjhoux, Isabelle Coupier, Francesca Damiola, Dominique Stoppa-Lyonnet, Claude Houdayer, Capucine Delnatte, Bruno Buecher, Brigitte Bressac-de Paillerets, Shan Wang-Gohrke, Barbara Wappenschmidt, Raymonda Varon-Mateeva, Norbert Arnold, Nina Ditsch, Kerstin Rhiem, Karin Kast, Hansjoerg Plendl, Doris Steinemann, Dieter Niederacher, Christoph Engel, Christian Sutter, Andrea Gehrig, Alfons Meindl, Tom Van Maerken, Kathleen Claes, Andrew K. Godwin, Trevor Cole, Steve Ellis, Shirley V. Hodgson, Rosemarie Davidson, Radka Platte, Patrick J. Morrison, Mary E. Porteous, Mark T. Rogers, M. John Kennedy, Lucy E. Side, Louise Izatt, Lisa Walker, Julian Barwell, Julian Adlard, Marc Tischkowitz, Jackie Cook, Angela Brady, Diana Eccles, Debra Frost, D. Gareth R. Evans, Claire Foo, Carole Brewer, Alan Donaldson, Judy E. Garber, Florentia Fostira, Athanassios Vratimos, Paolo Radice, Maria Grazia Tibiletti, Aline Martayan, Laura Papi, Giuseppe Giannini, Alessandra Viel, Stefano Fortuzzi, Frederique Mariette, Filomena Ficarazzi, Monica Barile, Giulietta Scuvera, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Jeffrey N. Weitzel, Kathleen R. Blazer, Edye E. Conway, Javier Benitez, Cristina Martínez-Bouzas, Ana Osorio, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Thomas V.O. Hansen, Susan L. Neuhausen, Yuan Chun Ding, Elizabeth J. van Rensburg, Cecilia M. Dorfling, Ramunas Janavicius, Saundra S. Buys, David E. Goldgar, Melissa C. Southey, Alex Miron, Wendy K. Chung, Jenny Lester, Sandra Orsulic, Beth Y. Karlan, Banu K. Arun, Timothy R. Rebbeck, Susan M. Domchek, Katherine L. Nathanson, Robert L. Nussbaum, Olufunmilayo I. Olopade, Encarna B. Gómez Garcia, Anna Jakubowska, Jan Lubinski, Laura Matricardi, Marco Montagna, Ana-Teresa Maia, Felicity Lose, Logan C. Walker, Amanda B. Spurdle, Frederieke H. van der Baan, Marjanka K. Schmidt, Matti A. Rookus, Bowang Chen, Stefan Wilkening, Ute Hamann, Douglas F. Easton, Rosalind A. Eeles, Penny Soucy, Jacques Simard, Rita K. Schmutzler, Anja Rudolph, Kirsten B. Moysich, Jenny Chang-Claude, and Paolo Peterlongo
Abstract: Supplementary Table 3. Results of the statistical analyses of SNPs from project 12 in BRCA-mutation carriers affected or non-affected with breast cancer and according to their estrogen receptor status.
Published: 2023

13. Data from Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Eitan Friedman, Antonis C. Antoniou, Georgia Chenevix-Trench, Paul D.P. Pharoah, Andrew Lee, Sue Healey, Daniel Barrowdale, Lesley McGuffog, Karoline B. Kuchenbaecker, Åke Borg, Marie Stenmark Askmalm, Hans Ehrencrona, Anna von Wachenfeldt, Johanna Rantala, Yael Laitman, Uffe Birk Jensen, Mads Thomassen, Inge Sokilde Pedersen, Anders Bojesen, Amanda Ewart Toland, Irene L. Andrulis, Sandrine Tchatchou, Gord Glendon, Anna Marie Mulligan, Gad Rennert, Phuong L. Mai, Mark H. Greene, Catherine M. Phelan, Muy-Kheng M. Tea, Georg Pfeiler, Daphne Geschwantler Kaulich, Christine Rappaport, Christian F. Singer, Andreas Berger, Vijai Joseph, Liying Zhang, Mark E. Robson, Lauren Jacobs, Marina Corines, Kenneth Offit, Csilla I. Szabo, Xianshu Wang, Noralane M. Lindor, Fergus J. Couch, Curtis Olswold, Manuel R. Teixeira, Jocelyne Chiquette, Adalgeir Arason, Grzegorz Sukiennicki, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Jacek Gronwald, Cezary Cybulski, Lidia Feliubadalo, Joan Brunet, Conxi Lazaro, Ignacio Blanco, Orland Diez, Edith Olah, J. Margriet Collée, Helena C. van Doorn, Margreet G.E.M. Ausems, Nicoline Hoogerbrugge, Maaike P.G. Vreeswijk, Annemarie H. van der Hout, Hanne E.J. Meijers-Heijboer, Theo A.M. van Os, Kristiina Aittomäki, Heli Nevanlinna, Pedro Perez Segura, Miguel de la Hoya, Larry J. Copeland, Gustavo C. Rodriguez, Michael L. Friedlander, Marion Piedmonte, Muriel Belotti, Sylvie Mazoyer, Pascal Pujol, Olivier Caron, Olga M. Sinilnikova, Nadia Boutry-Kryza, Lisa Golmard, Laurence Venat-Bouvet, Laure Barjhoux, Isabelle Coupier, Francesca Damiola, Dominique Stoppa-Lyonnet, Claude Houdayer, Capucine Delnatte, Bruno Buecher, Brigitte Bressac-de Paillerets, Shan Wang-Gohrke, Barbara Wappenschmidt, Raymonda Varon-Mateeva, Norbert Arnold, Nina Ditsch, Kerstin Rhiem, Karin Kast, Hansjoerg Plendl, Doris Steinemann, Dieter Niederacher, Christoph Engel, Christian Sutter, Andrea Gehrig, Alfons Meindl, Tom Van Maerken, Kathleen Claes, Andrew K. Godwin, Trevor Cole, Steve Ellis, Shirley V. Hodgson, Rosemarie Davidson, Radka Platte, Patrick J. Morrison, Mary E. Porteous, Mark T. Rogers, M. John Kennedy, Lucy E. Side, Louise Izatt, Lisa Walker, Julian Barwell, Julian Adlard, Marc Tischkowitz, Jackie Cook, Angela Brady, Diana Eccles, Debra Frost, D. Gareth R. Evans, Claire Foo, Carole Brewer, Alan Donaldson, Judy E. Garber, Florentia Fostira, Athanassios Vratimos, Paolo Radice, Maria Grazia Tibiletti, Aline Martayan, Laura Papi, Giuseppe Giannini, Alessandra Viel, Stefano Fortuzzi, Frederique Mariette, Filomena Ficarazzi, Monica Barile, Giulietta Scuvera, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Jeffrey N. Weitzel, Kathleen R. Blazer, Edye E. Conway, Javier Benitez, Cristina Martínez-Bouzas, Ana Osorio, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Thomas V.O. Hansen, Susan L. Neuhausen, Yuan Chun Ding, Elizabeth J. van Rensburg, Cecilia M. Dorfling, Ramunas Janavicius, Saundra S. Buys, David E. Goldgar, Melissa C. Southey, Alex Miron, Wendy K. Chung, Jenny Lester, Sandra Orsulic, Beth Y. Karlan, Banu K. Arun, Timothy R. Rebbeck, Susan M. Domchek, Katherine L. Nathanson, Robert L. Nussbaum, Olufunmilayo I. Olopade, Encarna B. Gómez Garcia, Anna Jakubowska, Jan Lubinski, Laura Matricardi, Marco Montagna, Ana-Teresa Maia, Felicity Lose, Logan C. Walker, Amanda B. Spurdle, Frederieke H. van der Baan, Marjanka K. Schmidt, Matti A. Rookus, Bowang Chen, Stefan Wilkening, Ute Hamann, Douglas F. Easton, Rosalind A. Eeles, Penny Soucy, Jacques Simard, Rita K. Schmutzler, Anja Rudolph, Kirsten B. Moysich, Jenny Chang-Claude, and Paolo Peterlongo
Abstract: Background:BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes.Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.
Published: 2023

14. Supplementary Methods, Tables 1-3, Figure 1 from Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

Author: Douglas F. Easton, Georgia Chenevix-Trench, Radka Platte, Xiaoqing Chen, Helene Holland, Amanda B. Spurdle, Jacques Simard, Heli Nevanlinna, Kristiina Aittomäki, Miguel de la Hoya, Trinidad Caldes, Ines Schönbuchner, Karin Kast, Sabine Preisler-Adams, Dorothea Gadzicki, Helmut Deissler, Christian Sutter, Dieter Niederacher, Raymonda Varon-Mateeva, Simone Heidemann, Norbert Arnold, Magdalena Lochmann, Alfons Meindl, Christoph Engel, Barbara Wappenschmidt, Rita Schmutzler, Jenny Gross, Beth Y. Karlan, Lara Sucheston, Susan J. Ramus, Conxi Lazaro, Ignacio Blanco, Laima Tihomirova, Evgeny Imyanitov, Cinzia Casella, Marco Montagna, Amanda Ewart Toland, Stephanie V. Blank, Peter E. Schwartz, Jack Basil, John F. Boggess, Katie Wakeley, Gustavo C. Rodriguez, Marion Piedmonte, Ana Dutra-Clarke, Vincent Devlin, Kenneth Offit, Tomas Kirchhoff, Bjarni A. Agnarsson, Lars Jønson, Thomas V.O. Hansen, Georg Pfeiler, Daphne Gschwantler-Kaulich, Anne Catharina Dressler, Christian F. Singer, David Goldgar, Alexander Miron, Yosuf Yassin, Saundra S. Buys, Esther M. John, Mary B. Terry, Mary B. Daly, John L. Hopper, Laurence Vénat-Bouvet, Marc Frénay, Catherine Nogues, Etienne Rouleau, Hagay Sobol, Tetsuro Noguchi, Catherine Loustalot, Laurence Faivre, Pascaline Berthet, Agnès Hardouin, Dominique Leroux, Hélène Dreyfus, Christine Lasset, Valérie Bonadona, Sylvie Mazoyer, Antoine de Pauw, Dominique Stoppa-Lyonnet, Andrew K. Godwin, Susan Peock, Huw Dorkins, M. John Kennedy, Lisa Walker, Mary E. Porteous, Patrick J. Morrison, Shirley Hodgson, Joan Paterson, Jackie Cook, Trevor Cole, Rosemarie Davidson, Gabriella Pichert, Fiona Lalloo, D. Gareth Evans, Don Conroy, Debra Frost, Clare Oliver, Margaret Cook, Matti Rookus, Frans Hogervorst, Cora M. Aalfs, Marinus J. Blok, E.J. Meijers-Heijboer, Peter Devilee, Christi J. van Asperen, Rob B. van der Luijt, Nicoline Hoogerbrugge, Mieke Kriege, Ute Hamann, Javier Benitez, Javier Godino, Maria-Isabel Tejada, Mercedes Durán, Adriana Lasa, Ana Osorio, Tomasz Huzarski, Jan Lubinski, Ania Jakubowska, Susan Domchek, Kate Nathanson, Beatrice Melin, Marie Stenmark-Askmalm, Johanna Rantala, Annika Lindblom, Helena Jernström, Ake Borg, Shimrit Cohen, Maya Dubrovsky, Roni Milgrom, Yael Laitman, Bella Kaufman, Eitan Friedman, Maria Caligo, Uffe Birk Jensen, Dorthe Cruger, Lone Sunde, Anne-Marie Gerdes, Mads Thomassen, Irene L. Andrulis, Hilmi Ozcelik, Gord Glendon, Flavio Lejbkowicz, Gad Rennert, Mark H. Greene, Phuong L. Mai, Lenka Foretova, Bruce Poppe, Kathleen Claes, Michal Zikan, Csilla I. Szabo, Paolo Peterlongo, Valentina Dall'Olio, Anna Allavena, Alessandra Viel, Monica Barile, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Paolo Radice, Vernon S. Pankratz, Noralane M. Lindor, Xianshu Wang, Fergus J. Couch, Olufunmilayo I. Olopade, Gail Tomlinson, Patricia A. Ganz, Claudine Isaacs, Henry T. Lynch, Jeffrey N. Weitzel, Timothy R. Rebbeck, Yuan Chun Ding, Susan L. Neuhausen, Sue Healey, Olga M. Sinilnikova, Lesley McGuffog, Jonathan Beesley, and Antonis C. Antoniou
Abstract: Supplementary Methods, Tables 1-3, Figure 1 from Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction
Published: 2023

15. Kosaki overgrowth syndrome: A novel pathogenic variant in <scp> PDGFRB </scp> and expansion of the phenotype including cerebrovascular complications

Author: Diana Johnson, Jonathan Ellenbogen, Elise Schaefer, Annie Joseph, Gavin Ryan, Ange-Line Bruel, Celia Moss, Rebecca Keelagher, Bethanie Rooke, Alison Foster, Harriet Walker, Pierre Vabres, Quentin Thomas, Trevor Cole, Andrea Jester, Thalia Antoniadi, Rebecca Igbokwe, Maxime Luu, Véronique Quenardelle, Basile Chalot, Christophe Philippe, Arthur Sorlin, Laurence Faivre, Valérie Wolff, Derek Lim, Jessica Woodley, Marc Bardou, and Christel Thauvin-Robinet
Subjects: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Infantile myofibromatosis, PDGFRB, Scoliosis, 030105 genetics & heredity, Craniosynostosis, Receptor, Platelet-Derived Growth Factor beta, 03 medical and health sciences, Camptodactyly, Genetics, medicine, Humans, Joint dislocation, Stroke, Growth Disorders, Genetics (clinical), business.industry, Genetic Variation, Middle Aged, medicine.disease, Cerebrovascular Disorders, Phenotype, 030104 developmental biology, medicine.symptom, Lipodystrophy, business
Abstract: Heterozygous activating variants in platelet-derived growth factor, beta (PDGFRB) are associated with phenotypes including Kosaki overgrowth syndrome (KOGS), Penttinen syndrome and infantile myofibromatosis (IM). Here, we present three new cases of KOGS, including a patient with a novel de novo variant c.1477A > T p.(Ser493Cys), and the oldest known individual age 53 years. The KOGS phenotype includes characteristic facial features, tall stature, scoliosis, hyperelastic thin skin, lipodystrophy, variable intellectual and neurological deterioration, and abnormalities on brain imaging. Long-term outcome is unknown. Our cases confirm the phenotypic spectrum includes progressive flexion contractures, camptodactyly, widely spaced teeth, and constriction rings. We also propose novel occasional features including craniosynostosis, ocular pterygia, anterior chamber cleavage syndrome, early osteoporosis, increased pigmentation, recurrent haematomas, predisposition to cellulitis, nail dystrophy, carpal tunnel syndrome, recurrent hypoglycaemia in infancy, joint dislocation, and splenomegaly. Importantly, we report fusiform aneurysm of the basilar artery in two patients. Complications include thrombosis and stroke in the oldest reported patient and fatal rupture at the age of 21 in the patient with the novel variant. We conclude that cerebrovascular complications are part of the phenotypic spectrum of KOGS and KOGS-like disorders and suggest vascular imaging is indicated in these patients.
Published: 2020

16. Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Author: Ashley N. Sigafoos, Salima El Chehadeh, Marcia C. Willing, Ela Akay, Florian Cherik, Anne-Marie E. Goyette, Vinodh Narayanan, Diane Masser-Frye, Catherine Karimov, Rhonda E. Schnur, Rebekah Bressi, Rhys H. Thomas, Gary D. Clark, Tina Barbaro-Dieber, Jill A. Rosenfeld, Carlos A. Bacino, Maria J. Guillen Sacoto, Laura Russell, Kristin Lindstrom, Caroline Schluth-Bolard, Xia Wang, Yvonne Hilhorst-Hofstee, Marcelo Vargas, Zehua Zhu, Ash Zawerton, Boris Keren, Mariëtte J.V. Hoffer, Isabelle Marey, Alice Poisson, Daphné Lehalle, Maries Joseph, Gaetan Lesca, Simon Zwolinski, Laurence Perrin, Rhoda Akilapa, Emilia K. Bijlsma, Christel Depienne, Amélie Piton, Claire G. Salter, Lucie Dupuis, Daryl A. Scott, Jolien S. Klein Wassink-Ruiter, Benjamin Cogné, Mathilde Nizon, Richard Chang, Kirsty McWalter, Myriam Srour, Perrine Charles, Anne-Claude Tabet, Natalie Canham, Sylvie Odent, Caroline Nava, Karl J. Clark, Elizabeth J. Bhoj, Jonathan Levy, Keri Ramsey, Yves Alembik, Lucia Ortega, Sophie Dupuis-Girod, Shoji Ichikawa, Christine Francannet, Marta Bertoli, Christèle Dubourg, Eric W. Klee, Ange-Line Bruel, Sebastien Moutton, Emily Fassi, Anthony Vandersteen, Abdul Haseeb, Antonina Wojcik, Patrick R. Blackburn, Lynne M. Bird, Patrick Rump, Véronique Lefebvre, Alma Kuechler, Sophie Nambot, Keren Machol, Cyril Mignot, Andreas Hartmann, Rossana Sanchez Russo, Erica H. Gerkes, Sylvie Jaillard, Roberto Mendoza-Londono, Trevor Cole, Pauline Monin, Cleveland Clinic, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), 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 ), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, This research was funded in part by the Agence Nationale de la Recherche and European High-Functioning Autism Network (ANR EUHFAUTISM), the Assistance Publique–Hôpitaux de Paris (AP-HP), the Institut National de la Santé et de la Recherche Médicale (INSERM), the BioPsy labex (to Christel Depienne and C.N.) and the Association Française du Syndrome Gilles de la Tourette (AFSGT) to Christel Depienne. It was also funded by the Cleveland Clinic Lerner Research Institute (LRI Chair’s Innovative Research Award to V.L.), and by Harper’s Quest and the LAMSHF Syndrome Research Fund (donations to V.L.) and the Center for Individualized Medicine, Mayo Clinic. This study makes use of data generated by the DECIPHER community and the Deciphering Developmental Disorders (DDD) Study, which is funded by the Wellcome Trust. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network., We thank the patients and their families for their participation in this study, and the C4RCD Research Group (Newell Belnap, Amanda Courtright, Ana Claasen, David Craig, Matt Huentelman, Madison LaFleur, Sampathkumar Rangasamy, Ryan Richholt, Isabelle Schrauwen, Ashley L. Siniard, and Szabolics Szelinger) for providing clinical information on patient P18., Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Centre d'Exploration et de Recherche Médicales par Émission de Positons (CERMEP), Université Joseph Fourier - Grenoble 1 (UJF)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Medizin, Haploinsufficiency, L-SOX5, VARIANTS, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Missense mutation, 2.1 Biological and endogenous factors, Aetiology, Child, Genetics (clinical), Genetics, Pediatric, Genetics & Heredity, 0303 health sciences, Pedigree, FAMILY, DNA-Binding Proteins, developmental delay, TRANSCRIPTION FACTORS, Phenotype, intellectual disability, Child, Preschool, missense variants, Female, SOXD Transcription Factors, Adult, EXPRESSION, Adolescent, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Mutation, Missense, autism, Cell fate determination, Biology, LONG FORM, SEQUENCE, Article, 03 medical and health sciences, Young Adult, Rare Diseases, Clinical Research, CARTILAGE, Intellectual Disability, medicine, Animals, Humans, Language Development Disorders, Genetic Predisposition to Disease, Preschool, Transcription factor, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MUTATIONS, Human Genome, Infant, medicine.disease, Brain Disorders, Neurodevelopmental Disorders, Deciphering Developmental Disorder Study, Mutation, Autism, epilepsy, Missense, 030217 neurology & neurosurgery, GENERATION
Abstract: International audience; PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types of SOX5 alterations. Functional consequences of selected substitutions were investigated.RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.CONCLUSIONS:This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.
Published: 2020

17. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study

Author: Elizabeth K Bancroft, Elizabeth C Page, Mark N Brook, Sarah Thomas, Natalie Taylor, Jennifer Pope, Jana McHugh, Ann-Britt Jones, Questa Karlsson, Susan Merson, Kai Ren Ong, Jonathan Hoffman, Camilla Huber, Lovise Maehle, Eli Marie Grindedal, Astrid Stormorken, D Gareth Evans, Jeanette Rothwell, Fiona Lalloo, Angela F Brady, Marion Bartlett, Katie Snape, Helen Hanson, Paul James, Joanne McKinley, Lyon Mascarenhas, Sapna Syngal, Chinedu Ukaegbu, Lucy Side, Tessy Thomas, Julian Barwell, Manuel R Teixeira, Louise Izatt, Mohnish Suri, Finlay A Macrae, Nicola Poplawski, Rakefet Chen-Shtoyerman, Munaza Ahmed, Hannah Musgrave, Nicola Nicolai, Lynn Greenhalgh, Carole Brewer, Nicholas Pachter, Allan D Spigelman, Ashraf Azzabi, Brian T Helfand, Dorothy Halliday, Saundra Buys, Teresa Ramon y Cajal, Alan Donaldson, Kathleen A Cooney, Marion Harris, John McGrath, Rosemarie Davidson, Amy Taylor, Peter Cooke, Kathryn Myhill, Matthew Hogben, Neil K Aaronson, Audrey Ardern-Jones, Chris H Bangma, Elena Castro, David Dearnaley, Alexander Dias, Tim Dudderidge, Diana M Eccles, Kate Green, Jorunn Eyfjord, Alison Falconer, Christopher S Foster, Henrik Gronberg, Freddie C Hamdy, Oskar Johannsson, Vincent Khoo, Hans Lilja, Geoffrey J Lindeman, Jan Lubinski, Karol Axcrona, Christos Mikropoulos, Anita V Mitra, Clare Moynihan, Holly Ni Raghallaigh, Gad Rennert, Rebecca Collier, Judith Offman, Zsofia Kote-Jarai, Rosalind A Eeles, Lisa Adams, Julian Adlard, Rosa Alfonso, Saira Ali, Angela Andrew, Luís Araújo, Nazya Azam, Darran Ball, Queenstone Barker, Alon Basevitch, Barbara Benton, Cheryl Berlin, Nicola Bermingham, Leah Biller, Angela Bloss, Matilda Bradford, Nicola Bradshaw, Amy Branson, Charles Brendler, Maria Brennan, Barbara Bulman, Lucy Burgess, Declan Cahill, Alice Callard, Nuria Calvo Verges, Marta Cardoso, Vanda Carter, Mario Catanzaro, Anthony Chamberlain, Cyril Chapman, Michael Chong, Caroline Clark, Virginia Clowes, Lyn Cogley, Trevor Cole, Cecilia Compton, Tom Conner, Sandra Cookson, Philip Cornford, Philandra Costello, Laura Coulier, Michaela Davies, Christopher Dechet, Bianca DeSouza, Gemma Devlin, Fiona Douglas, Emma Douglas, Darshna Dudakia, Alexis Duncan, Natalie Ellery, Sarah Everest, Sue Freemantle, Mark Frydenberg, Debbie Fuller, Camila Gabriel, Madeline Gale, Lynda Garcia, Simona Gay, Elena Genova, Angela George, Demetra Georgiou, Alexandra Gisbert, Margaret Gleeson, Wayne Glover, Vincent Gnanapragasam, Sally Goff, David Goldgar, Nuno Gonçalves, Selina Goodman, Jennifer Gorrie, Hannah Gott, Anna Grant, Catherine Gray, Julie Griffiths, Karin Gupwell, Jana Gurasashvili, Eldbjørg Hanslien, Sigurdis Haraldsdottir, Rachel Hart, Catherine Hartigan, Lara Hawkes, Tricia Heaton, Alex Henderson, Rui Henrique, Kathrine Hilario, Kathryn Hill, Peter Hulick, Clare Hunt, Melanie Hutchings, Rita Ibitoye, Thomas Inglehearn, Joanna Ireland, Farah Islam, Siti Ismail, Chris Jacobs, Denzil James, Sharon Jenkins, Irene Jobson, Anne Johnstone, Oliver Jones, Sagi Josefsberg Ben-Yehoshua, Beckie Kaemba, Karen Kaul, Zoe Kemp, Netty Kinsella, Margaret Klehm, Roger Kockelbergh, Kelly Kohut, Monika Kosicka-Slawinska, Anjana Kulkarni, Pardeep Kumar, Jimmy Lam, Mandy LeButt, Dan Leibovici, Ramona Lim, Lauren Limb, Claire Lomas, Mark Longmuir, Consol López, Tiziana Magnani, Sofia Maia, Jessica Maiden, Alison Male, Merrie Manalo, Phoebe Martin, Donna McBride, Michael McGuire, Romayne McMahon, Claire McNally, Terri McVeigh, Ehud Melzer, Mark Mencias, Catherine Mercer, Gillian Mitchell, Josefina Mora, Catherine Morton, Cathryn Moss, Morgan Murphy, Declan Murphy, Shumi Mzazi, Maria Nadolski, Anna Newlin, Pedro Nogueira, Rachael O'Keefe, Karen O'Toole, Shona O'Connell, Chris Ogden, Linda Okoth, Jorge Oliveira, Edgar Paez, Joan Palou, Linda Park, Nafisa Patel, João Paulo Souto, Allison Pearce, Ana Peixoto, Kimberley Perez, Lara Petelin, Gabriella Pichert, Charlotte Poile, Alison Potter, Nadia Preitner, Helen Purnell, Ellen Quinn, Paolo Radice, Brigette Rankin, Katie Rees, Caroline Renton, Kate Richardson, Peter Risby, Jason Rogers, Maggie Ruderman, April Ruiz, Anaar Sajoo, Natale Salvatore, Victoria Sands, Francesco Sanguedolce, Ayisha Sattar, Kathryn Saunders, Lyn Schofield, Rodney Scott, Anne Searle, Ravinder Sehra, Christina Selkirk, Kylie Shackleton, Sue Shanley, Adam Shaw, Daniel Shevrin, Hannah Shipman, Zahirah Sidat, Kas Siguake, Kate Simon, Courtney Smyth, Lesley Snadden, Nita Solanky, Joyce Solomons, Margherita Sorrentino, Barbara Stayner, Robert Stephenson, Elena Stoffel, Maggie Thomas, Alan Thompson, Lizzie Tidey, Marc Tischkowitz, Audrey Torokwa, Sharron Townshend, Katy Treherne, Karen Tricker, Quoc-Dien Trinh, Vishakha Tripathi, Clare Turnbull, Riccardo Valdagni, Nicholas Van As, Vickie Venne, Lizzie Verdon, Marco Vitellaro, Kristen Vogel, Lisa Walker, Amy Watford, Cathy Watt, Ilana Weintroub, Shelly Weiss, Scott Weissman, Michelle Weston, Jennifer Wiggins, Gillian Wise, Christopher Woodhouse, Pembe Yesildag, Alice Youngs, Matthew Yurgelun, Fabiana Zollo, Urology, Brook, Mark N [0000-0002-8969-2378], and Apollo - University of Cambridge Repository
Subjects: Oncology, Adult, Male, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Heterozygote, Prostate biopsy, Urology, Prostate-Specific Antigen/blood, DNA Mismatch Repair/genetics, DNA Mismatch Repair, Prostate cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Biomarkers, Tumor, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Prospective Studies, Prospective cohort study, Early Detection of Cancer, Germ-Line Mutation, Aged, Prostatic Neoplasms/diagnosis, medicine.diagnostic_test, business.industry, Endometrial cancer, Incidence, Cancer, Prostatic Neoplasms, Articles, Prostate-Specific Antigen, Middle Aged, medicine.disease, Lynch syndrome, digestive system diseases, DNA-Binding Proteins, Prostate cancer screening, MutS Homolog 2 Protein, MSH2, Biomarkers, Tumor/blood, population characteristics, business, human activities, geographic locations, DNA-Binding Proteins/genetics, MutS Homolog 2 Protein/genetics
Abstract: Funder: Victorian Cancer Agency, Funder: NIHR Manchester Biomedical Research Centre, Funder: Cancer Research UK, Funder: Cancer Council Tasmania, Funder: Instituto de Salud Carlos III, Funder: Cancer Australia, Funder: NIHR Oxford Biomedical Research Centre, Funder: Fundación Científica de la Asociación Española Contra el Cáncer, Funder: Cancer Council South Australia, Funder: Swedish Cancer Society, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Institut Català de la Salut, Funder: Cancer Council Victoria, Funder: Prostate Cancer Foundation of Australia, Funder: National Institutes of Health, BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.
Published: 2021

18. The hydrochemical signature of incongruent weathering in Iceland

Author: Preston Kemeny, Mark Torres, and Trevor Cole
Subjects: Geophysics, Earth-Surface Processes
Abstract: Basaltic watersheds such as those found in Iceland are thought to be important sites of CO₂ sequestration via silicate weathering. However, determining the magnitude of CO₂ uptake depends on accurately interpreting river chemistry. Here, we compile geochemical data from Iceland and use them to constrain weathering processes. Specifically, we use a newly developed inverse model to quantify solute supply from rain and hydrothermal fluids as well as allow for different mineral phases within basalts to react at different rates, solutes to be removed via clay formation, and some Ca to be sourced from carbonate dissolution. While some of these processes have been considered previously, they have not been considered together allowing us to newly determine their relative contributions.We find that weathering in Iceland is incongruent in two ways. Firstly, solute release from primary silicates is characterized by a higher proportion of Na than would be expected from bulk basalts, which may reflect preferential weathering or some contribution from rhyolites. This Na enrichment is further enhanced by preferential Mg and K uptake by clays. No samples in our dataset (n=537) require carbonate dissolution even if isotopic data (δ26Mg, δ30Si, δ44Ca, and/or 87Sr/86Sr) are included. While some carbonate weathering is allowable, silicate weathering likely dominates. The complexity we observe in Iceland underscores the need for inverse models to account for a wide range of processes and end-members. Given that riverine fluxes from Iceland are more Na-rich than expected for congruent basalt weathering, the characteristic timescale of CO₂ drawdown is likely affected.
Published: 2021

19. Genetic testing in inherited endocrine disorders: joint position paper of the European reference network on rare endocrine conditions (Endo-ERN)

Author: Eggermann T., Elbracht M., Kurth I., Juul A., Johannsen T. H., Netchine I., Mastorakos G., Johannsson G., Musholt T. J., Zenker M., Prawitt D., Pereira A. M., Hiort O., Stefan Riedl, Birgit Rami-Merhar, Greisa Vila, Sabina Baumgartner-Parzner, Walter Bonfig, Claudine Heinrichs, Dominique Maiter, Inge Gies, Martine Cools, Kristina Casteels, Albert Beckers, Sabina Zacharieva, Violeta Iotova, Tomislav Jukic, Dario Rahelic, Vassos Neocleous, Leonidas Phylactou, Michal Krsek, Jan Lebl, Claus Gravholt, Anders Juul, Vallo Tillmann, Vallo Volke, Tapani Ebeling, Thierry Brue, Patrice Rodien, Jérôme Bertherat, Christine Poitou Bernert, Philippe Touraine, Philippe Chanson, Michel Polak, Maithe Tauber, Thomas Eggermann, Joachim Spranger, Dagmar Fuhrer, Thomas Danne, Olaf Hiort, Klaus Mohnike, Dirk Prawitt, Markus Luster, Nicole Reisch, Martin Reincke, Julia Rohayem, Martin Fassnacht, Miklós Tóth, Alessandra Cassio, Sonia Toni, Csilla Krausz, Barbara Piccini, Diego Ferone, Gianni Russo, Luca Persani, Annamaria Colao, Mariacarolina Salerno, Marco Boscaro, Carla Scaroni, Ferruccio Santini, Giovanni Ceccarini, Ezio Ghigo, Iveta Dzivite-Krisane, Vita Rovite, Lauma Janozola, Rasa Verkauskiene, Michael Witsch, James Clark, Johannes Romijn, Thera Links, Nienke Biermasz, Sabine Hannema, Bas Havekes, Hedi Claahsen-van der Grinten, Henri Timmers, Robin Peeters, Gerlof Valk, A A Verrijn Stuart, Harm Haak, Eystein Husebye, Jens Bollerslev, Barbara Jarzab, Agnieszka 'Szypowska, João-Filipe Raposo, Dana Craiu, Doina Piciu, Ludmila Kostalova, Jarmila Vojtková, Tadej Battelino, Roque Cardona-Hernandez, Diego Yeste, Sonia Gaztambide, Anna Nordenström, Neil Gittoes, Trevor Cole, Elizabeth Crowne, Faisal Ahmed, Mohammed Didi, Marta Korbonits, Mehul Dattani, Peter Clayton, Justin Davies, Eggermann, T., Elbracht, M., Kurth, I., Juul, A., Johannsen, T. H., Netchine, I., Mastorakos, G., Johannsson, G., Musholt, T. J., Zenker, M., Prawitt, D., Pereira, A. M., Hiort, O, Salerno, M, Clinical sciences, Growth and Development, Pediatrics, Eggermann T., Elbracht M., Kurth I., Juul A., Johannsen T.H., Netchine I., Mastorakos G., Johannsson G., Musholt T.J., Zenker M., Prawitt D., Pereira A.M., and Hiort O., Stefan Riedl, Birgit Rami-Merhar, Greisa Vila, Sabina Baumgartner-Parzner, Walter Bonfig, Claudine Heinrichs, Dominique Maiter, Inge Gies, Martine Cools, Kristina Casteels, Albert Beckers, Sabina Zacharieva, Violeta Iotova, Tomislav Jukic, Dario Rahelic, Vassos Neocleous, Leonidas Phylactou, Michal Krsek, Jan Lebl, Claus Gravholt, Anders Juul, Vallo Tillmann, Vallo Volke, Tapani Ebeling, Thierry Brue, Patrice Rodien, Jérôme Bertherat, Christine Poitou Bernert, Philippe Touraine, Philippe Chanson, Michel Polak, Maithe Tauber, Thomas Eggermann, Joachim Spranger, Dagmar Fuhrer, Thomas Danne, Olaf Hiort, Klaus Mohnike, Dirk Prawitt, Markus Luster, Nicole Reisch, Martin Reincke, Julia Rohayem, Martin Fassnacht, Miklós Tóth, Alessandra Cassio, Sonia Toni, Csilla Krausz, Barbara Piccini, Diego Ferone, Gianni Russo, Luca Persani, Annamaria Colao, Mariacarolina Salerno, Marco Boscaro, Carla Scaroni, Ferruccio Santini, Giovanni Ceccarini, Ezio Ghigo, Iveta Dzivite-Krisane, Vita Rovite, Lauma Janozola, Rasa Verkauskiene, Michael Witsch, James Clark, Johannes Romijn, Thera Links, Nienke Biermasz, Sabine Hannema, Bas Havekes, Hedi Claahsen-van der Grinten, Henri Timmers, Robin Peeters, Gerlof Valk, A A Verrijn Stuart, Harm Haak, Eystein Husebye, Jens Bollerslev, Barbara Jarzab, Agnieszka 'Szypowska, João-Filipe Raposo, Dana Craiu, Doina Piciu, Ludmila Kostalova, Jarmila Vojtková, Tadej Battelino, Roque Cardona-Hernandez, Diego Yeste, Sonia Gaztambide, Anna Nordenström, Neil Gittoes, Trevor Cole, Elizabeth Crowne, Faisal Ahmed, Mohammed Didi, Marta Korbonits, Mehul Dattani, Peter Clayton, Justin Davies
Subjects: 0301 basic medicine, Genetic testing, disorders of sex development, PREDICTION, lcsh:Medicine, CHILDREN, Review, VARIANTS, Hypogonadotropic hypogonadism, Imprinting disorder, 0302 clinical medicine, Pharmacology (medical), Genetics (clinical), Imprinting disorders, Rare endocrine conditions, Short stature - glucose and insulin homeostasis - Hypogonadotropic hypogonadism - differences/disorders of sex development, Medicine(all), RISK, medicine.diagnostic_test, CHALLENGES, differences, High-Throughput Nucleotide Sequencing, General Medicine, genetic testing, Imprinting disorders, Rare endocrine conditions, Short stature, glucose and insulin homeostasis, Hypogonadotropic hypogonadism, disorders of sex development, Mutation (genetic algorithm), Rare endocrine condition, Identification (biology), Genetic counseling, 030209 endocrinology & metabolism, Computational biology, DIAGNOSIS, Endocrine System Diseases, differences/disorders of sex development, 03 medical and health sciences, Rare Diseases, BECKWITH-WIEDEMANN SYNDROME, medicine, MANAGEMENT, Endocrine system, Humans, business.industry, Network on, lcsh:R, glucose and insulin homeostasis, Human genetics, Short stature, 030104 developmental biology, Mutation, Position paper, business, Short stature - glucose and insulin homeostasis
Abstract: Orphanet journal of rare diseases: OJRD 15(1), 144 (2020). doi:10.1186/s13023-020-01420-w, Published by BioMed Central, London
Published: 2020
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20. Genetic Aspects of Endocrine Disease

Author: Trevor Cole
Abstract: In 1953, when Watson and Crick published their paper on the double helical structure of DNA, it would have been difficult to foresee the future impact this would have on clinical care, and unlikely anyone would have predicted the relatively slow progress over the subsequent 33 years compared to rapidity of change in the last decade. The current speed and low cost of molecular genetic analysis means that genomic testing now has the potential to provide diagnostic answers, individualized care (often described as personalized or precision treatment) and clear guidance for members of the extended family, in a timely manner for many patients with acute disease episodes or complex rare disorders. The challenge now to health provision across the globe is to interpret and manage appropriately the huge amount of data generated, and develop a workforce and service structures which can deliver this technology in an efficient, effective, and equitable manner. Understanding how genes may act directly on one or multiple glands, often with the ability to result in hyperfunction and hypofunction in a mutation dependent manner or alternatively modify the action of multiple genes in a complex pathway has had a major impact on our understanding in endocrinology and will be illustrated in the following chapters. This review will provide some historical background and identify how the field of genomics will continue to impact of clinical practice in Endocrinology and Diabetes, as well as addressing some of the challenges and barriers that need to be overcome.
Published: 2021

21. Null variants and deletions in BRWD3 cause an X‐linked syndrome of mild–moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients

Author: Sahar Mansour, Sarah F. Smithson, Gillian Rea, Anna Zachariou, Philip J. Ostrowski, Edward Blair, Alison Foster, Sofia Douzgou, Katrina Tatton-Brown, Trevor Cole, Chey Loveday, Elizabeth Thompson, Swati Naik, Diana Baralle, Katherine Lachlan, Michael Field, Claire Kyle, and Yves Sznajer
Subjects: Male, 0301 basic medicine, Joint hypermobility, Pediatrics, medicine.medical_specialty, Adolescent, Context (language use), 030105 genetics & heredity, Severity of Illness Index, 03 medical and health sciences, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Prognathism, Obesity, Child, Genetics (clinical), business.industry, Macrocephaly, Genetic Diseases, X-Linked, Syndrome, medicine.disease, Megalencephaly, Chin, 030104 developmental biology, medicine.anatomical_structure, Neonatal hypotonia, medicine.symptom, Differential diagnosis, business, Gene Deletion, Transcription Factors
Abstract: BRWD3 has been described as a cause of X-linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and two partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (
Published: 2019

22. The phenotype of Sotos syndrome in adulthood: A review of 44 individuals

Author: Nayana Lahiri, Katrina Tatton-Brown, Edward Blair, Trevor Cole, Julie Vogt, Emma McCann, Sally Ann Lynch, Anna Zachariou, Shelagh Joss, Jenny Morton, Tazeen Ashraf, Deborah J. Shears, Sahar Mansour, Elizabeth Thompson, Nicole Motton, Alex Henderson, Chey Loveday, Blanca Gener, Katie Riches, Melita Irving, Huw Dorkins, Alan Fryer, Jill Clayton-Smith, David Goudie, Alexandra Murray, Zornitza Stark, Vaughan Keeley, Alison Foster, and Michael Wright
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Hearing loss, Scoliosis, Intellectual Disability, Intellectual disability, Genetics, Humans, Medicine, Child, Genetics (clinical), Muscle contracture, Sotos Syndrome, business.industry, Sotos syndrome, Macrocephaly, Facies, Tall Stature, medicine.disease, Phenotype, Lymphedema, Female, medicine.symptom, business
Abstract: Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.
Published: 2019

23. Hypothalamic Reproductive Endocrine Pulse Generator Activity Independent of Neurokinin B and Dynorphin Signaling

Author: Trevor Cole, Rajae Talbi, Margaret F. Lippincott, E. Terasawa, Yee-Ming Chan, Natalie D. Shaw, Janet E. Hall, Chrysanthi Fergani, Susan E. Stewart, S. Leon, I. S. Farooqi, Christopher M. Jones, Wiebke Arlt, Stephanie B. Seminara, and Víctor M. Navarro
Subjects: Neurokinin B, Narcotic Antagonists, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, (+)-Naloxone, Dynorphin, Substance P, Biochemistry, Gonadotropin-Releasing Hormone, Mice, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Kisspeptin, Opioid receptor, Child, Mice, Knockout, Neurons, Academic Medical Centers, Kisspeptins, 0303 health sciences, Treatment Outcome, Female, hormones, hormone substitutes, and hormone antagonists, Signal Transduction, Adult, medicine.medical_specialty, Adolescent, medicine.drug_class, Neuropeptide, 030209 endocrinology & metabolism, Context (language use), Biology, Dynorphins, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Animals, Humans, Clinical Research Articles, 030304 developmental biology, Hypogonadism, Biochemistry (medical), Luteinizing Hormone, Disease Models, Animal, nervous system, chemistry, Case-Control Studies, Blood sampling
Abstract: Context Kisspeptin–neurokinin B (NKB)–dynorphin neurons are critical regulators of the hypothalamic–pituitary–gonadal axis. NKB and dynorphin are hypothesized to influence the frequency of GnRH pulses, whereas kisspeptin is hypothesized to be a generator of the GnRH pulse. How these neuropeptides interact remains unclear. Objective To probe the role of NKB in GnRH pulse generation and to determine the interactions between NKB, kisspeptin, and dynorphin in humans and mice with a complete absence of NKB. Design Case/control. Setting Academic medical center. Participants Members of a consanguineous family bearing biallelic loss-of-function mutations in the gene encoding NKB and NKB-deficient mice. Interventions Frequent blood sampling to characterize neuroendocrine profile and administration of kisspeptin, GnRH, and naloxone, a nonspecific opioid receptor antagonist used to block dynorphin. Main Outcome Measures LH pulse characteristics. Results Humans lacking NKB demonstrate slow LH pulse frequency, which can be increased by opioid antagonism. Mice lacking NKB also demonstrate impaired LH secretion, which can be augmented with an identical pharmacologic manipulation. Both mice and humans with NKB deficiency respond to exogenous kisspeptin. Conclusion The preservation of LH pulses in the absence of NKB and dynorphin signaling suggests that both peptides are dispensable for GnRH pulse generation and kisspeptin responsiveness. However, NKB and dynorphin appear to have opposing roles in the modulation of GnRH pulse frequency.
Published: 2019

24. EED and EZH2 constitutive variants: A study to expand the Cohen-Gibson syndrome phenotype and contrast it with Weaver syndrome

Author: Sara Griffiths, Susan M. White, Mark Sherlock, Amanda Springer, Chiara Pantaleoni, Anna Zachariou, Trevor Cole, Edna Roche, Donatella Milani, Stefano D'Arrigo, Chey Loveday, Katrina Tatton-Brown, L. A. Behan, James Gibney, Andrea Dieckmann, Alison Foster, Matthew F. Hunter, and Kate Chandler
Subjects: Adult, Male, 0301 basic medicine, Microcephaly, Histone methyltransferase activity, Developmental Disabilities, 030105 genetics & heredity, Craniofacial Abnormalities, Fingers, Young Adult, 03 medical and health sciences, Intellectual Disability, Exome Sequencing, Intellectual disability, Congenital Hypothyroidism, Myopia, Genetics, medicine, Humans, Abnormalities, Multiple, Enhancer of Zeste Homolog 2 Protein, Obesity, Child, Growth Disorders, Genetics (clinical), Exome sequencing, Weaver syndrome, business.industry, Retinal Degeneration, EZH2, Polycomb Repressive Complex 2, medicine.disease, Congenital hypothyroidism, Phenotype, 030104 developmental biology, Overgrowth syndrome, Mutation, Muscle Hypotonia, Female, business, Hand Deformities, Congenital
Abstract: Overgrowth-intellectual disability (OGID) syndromes are characterized by increased growth (height and/or head circumference ≥+2 SD) in association with an intellectual disability. Constitutive EED variants have previously been reported in five individuals with an OGID syndrome, eponymously designated Cohen-Gibson syndrome and resembling Weaver syndrome. Here, we report three additional individuals with constitutive EED variants, identified through exome sequencing of an OGID patient series. We compare the EED phenotype with that of Weaver syndrome (56 individuals), caused by constitutive EZH2 variants. We conclude that while there is considerable overlap between the EED and EZH2 phenotypes with both characteristically associated with increased growth and an intellectual disability, individuals with EED variants more frequently have cardiac problems and cervical spine abnormalities, boys have cryptorchidism and the facial gestalts can usually be distinguished.
Published: 2019

25. Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD)

Author: Nils Krone, Liam McCarthy, Harish Chandran, Trevor Cole, Zainaba Mohamed, Samuel Clokie, P Dasani, Jeremy Kirk, K McKay-Bounford, Lowri Hughes, Stephanie Allen, and E A Webb
Subjects: lcsh:RC648-665, medicine.diagnostic_test, disorders of sex development (DSD), business.industry, Endocrinology, Diabetes and Metabolism, Research, Inheritance (genetic algorithm), next generation sequencing (NGS), Bioinformatics, medicine.disease, lcsh:Diseases of the endocrine glands. Clinical endocrinology, DNA sequencing, Patient management, Endocrinology, variant, Internal Medicine, Medicine, Disorders of sex development, Medical diagnosis, Genetic diagnosis, business, gene, Uncertain significance, Genetic testing
Abstract: Disorders of sex development (DSDs) are a diverse group of conditions where the chromosomal, gonadal or anatomical sex can be atypical. The highly heterogeneous nature of this group of conditions often makes determining a genetic diagnosis challenging. Prior to next generation sequencing (NGS) technologies, genetic diagnostic tests were only available for a few of the many DSD-associated genes, which consequently had to be tested sequentially. Genetic testing is key in establishing the diagnosis, allowing for personalised management of these patients. Pinpointing the molecular cause of a patient’s DSD can significantly impact patient management by informing future development needs, altering management strategies and identifying correct inheritance pattern when counselling family members. We have developed a 30-gene NGS panel, designed to be used as a frontline test for all suspected cases of DSD (both 46,XX and 46,XY cases). We have confirmed a diagnosis in 25 of the 80 patients tested to date. Confirmed diagnoses were linked to mutations in AMH, AMHR2, AR, HSD17B3, HSD3B2, MAMLD1, NR5A1, SRD5A2 and WT1 which have resulted in changes to patient management. The minimum diagnostic yield for patients with 46,XY DSD is 25/73. In 34/80 patients, only benign or likely benign variants were identified, and in 21/80 patients only variants of uncertain significance (VOUS) were identified, resulting in a diagnosis not being confirmed in these individuals. Our data support previous studies that an NGS panel approach is a clinically useful and cost-effective frontline test for patients with DSDs.
Published: 2019

26. Organic sulfur fluxes and geomorphic control of sulfur isotope ratios in rivers

Author: Samuel M. Webb, Michael P. Lamb, Mark A. Torres, P. C. Kemeny, Jess F. Adkins, Trevor Cole, Yi Hou, Nathan F. Dalleska, J. P. Marske, and Woodward W. Fischer
Subjects: 010504 meteorology & atmospheric sciences, chemistry.chemical_element, Fluvial, Sediment, Weathering, engineering.material, 010502 geochemistry & geophysics, 01 natural sciences, Sulfur, Carbon cycle, chemistry.chemical_compound, Geophysics, chemistry, Space and Planetary Science, Geochemistry and Petrology, Environmental chemistry, Earth and Planetary Sciences (miscellaneous), engineering, Alluvium, Pyrite, Sulfate, Geology, 0105 earth and related environmental sciences
Abstract: Pyrite oxidation plays a critical role in the relationship between weathering and climate, and its impact on the global carbon cycle has previously been constrained through inversion models utilizing observations of river sulfate (SO 4 2 − ) and its 34S/32S isotope ratio ( δ 34 SSO4). However, measurements from some rivers have suggested that δ 34 SSO4 can be substantially impacted by processes such as microbial sulfate reduction and/or sulfur assimilation and cycling, rather than simply reflecting a weighted mixture of lithologic sulfur sources. To study the prevalence and controls on SO 4 2 − transformations, we measured dissolved major element concentrations and δ 34 SSO4 in river water samples from throughout western Iceland. Our analyses focused on samples from a small catchment hosting the Efri Haukadalsa river, a system with relatively uniform and isotopically constrained basaltic bedrock. We also measured sediment δ 34 S and sulfur speciation using sulfur K-edge X-ray absorption spectroscopy on sediment and vegetation samples from this catchment. Values of dissolved δ 34 SSO4 in the Efri Haukadalsa ranged from 2.5‰ to 23.7‰ and had a linear relationship with Cl−/SO 4 2 − ratios, indicating that SO 4 2 − predominantly derived from basalt weathering and meteoric precipitation. The lower δ 34 SSO4 values were found in fluvial valleys with V-shaped cross sections, while higher values of δ 34 SSO4 occurred in U-shaped, glacially eroded valleys with thick alluvial fills blanketing the valley floor. Spectroscopic observations identified organic sulfur phases in suspended river sediment, floodplain deposits, and vegetation. Mass balance calculations quantified the organic sulfur flux as less than 10% of SO 4 2 − export, and sediment δ 34 S values were comparable to river δ 34 SSO4. We interpreted these isotopic and chemical patterns as reflecting differences in the availability of unweathered bedrock across the Efri Haukadalsa catchment, with V-shaped valleys having greater access to fresh sulfide-bearing minerals than alluviated U-shaped valleys; this interpretation is in contrast to one in which the elevated δ 34 SSO4 values reflect fractionation during sulfur transformations along alluvial reaches. These results validated the application of river inversion models for constraining weathering fluxes and affirmed that pyrite oxidation globally, even in the presence of river sulfur cycling, modulates the abundance of atmospheric carbon dioxide.
Published: 2021

27. Non-Invasive Prenatal Diagnosis of Retinoblastoma Inheritance by Combined Targeted Sequencing Strategies

Author: Trevor Cole, Maureen McCalla, Benjamin Bowns, Elizabeth Young, Sue Carless, David Goudie, Samantha Court, Samuel Clokie, Simon C Ramsden, Stephanie Allen, Michael Parks, Chipo Mashayamombe-Wolfgarten, Amy Gerrish, and Joshua Bott
Subjects: Non-Mendelian inheritance, non-invasive, lcsh:Medicine, Prenatal diagnosis, Bioinformatics, Article, retinoblastoma, cell-free DNA, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, medicine, Genetic testing, 0303 health sciences, Massive parallel sequencing, prenatal diagnosis, medicine.diagnostic_test, Retinoblastoma, business.industry, 030305 genetics & heredity, lcsh:R, General Medicine, Amplicon, medicine.disease, eye diseases, Cell-free fetal DNA, 030221 ophthalmology & optometry, business
Abstract: Retinoblastoma, the most common childhood eye cancer, presents in two forms: heritable or sporadic. Heritable retinoblastoma is caused by a germline mutation in the RB1 gene. Early diagnosis of children at risk of inheriting an RB1 mutation is crucial to achieve optimal clinical outcome. Currently, the majority of genetic testing is performed on newborns, which has multiple disadvantages for both families and the healthcare system. We have developed a non-invasive prenatal diagnosis (NIPD) service for retinoblastoma, available from 8 weeks&rsquo, gestation, which uses a combination of massively parallel sequencing (MPS) techniques, dependent on the inheritance model. Detection of paternal or suspected de novo RB1 variants is achieved through amplicon-based MPS. NIPD of a fetus at risk of maternal inheritance is performed using capture-based targeted sequencing and relative haplotype dosage analysis. In addition, we show proof of principle of how capture-based sequencing can be used for de novo variants unsuitable for amplicon-based testing. In total, we report the NIPD of 15 pregnancies, results of which show 100% concordance with all postnatal testing performed at the time of publication (n = 12) with remaining pregnancies ongoing. NIPD of retinoblastoma therefore offers a viable alternative to newborn genetic testing.
Published: 2020

28. Identification of clinical parameters predictive of ARMC5 mutation in a large cohort of primary bilateral macronodular adrenal hyperplasia (PBMAH) patients

Author: Laurence Guignat, Antoine Tabarin, Jean-Louis Sadoul, Rossella Libe, Marie-Odile North, Françoise Borson-Chazot, Wiebke Arlt, Marie-Christine Vantyghem, Lefebvre Hervé, Felix Beuschlein, Patricia Vaduva, Lionel Groussin, Stéphanie Espiard, Anna Angelousi, Karine Perlemoine, Anna Vaczlavik, Trevor Cole, Chabre Olivier, Guillaume Assié, Christin-Maitre Sophie, Ana Agapito, Jérôme Bertherat, Marie-Laure Raffin-Sanson, Lucas Bouys, Philippe Chanson, Thierry Brue, Matthias Kroiss, Marcus Quinkler, Martin Reincke, and Bruno Ragazzon
Subjects: Oncology, medicine.medical_specialty, business.industry, Macronodular Adrenal Hyperplasia, Internal medicine, Mutation (genetic algorithm), Medicine, Identification (biology), business, Large cohort
Published: 2020

29. EPCAM mutation update: Variants associated with congenital tufting enteropathy and Lynch syndrome

Author: Sandy Oesterreicher, Mamata Sivagnanam, Erick Hernandez, Daniel Agardh, Vered Pinsk, Sagar J. Pathak, Odul Egritas Gurkan, Christopher D. Putnam, Jozef Hertecant, Michael Yourshaw, Barun Das, Sandhia Naik, Lynn Greenhalgh, James L. Mueller, Ian R. Sanderson, Martin G. Martin, Trevor Cole, Baruch Yerushalmi, Kevin Okamoto, Irene Axelsson, and C. Richard Boland
Subjects: Models, Molecular, Infantile, Congenital, Models, Missense mutation, 2.1 Biological and endogenous factors, Aetiology, Genetics (clinical), genotype‐phenotype correlation, Cancer, protein modeling, Genetics & Heredity, 0303 health sciences, Mutation Update, 030305 genetics & heredity, 16. Peace & justice, Epithelial Cell Adhesion Molecule, Lynch syndrome, 3. Good health, in silico simulation, MutS Homolog 2 Protein, Medical genetics, DNA mismatch repair, Colorectal Neoplasms, Diarrhea, medicine.medical_specialty, Clinical Sciences, Mutation, Missense, Biology, genotype-phenotype correlation, Frameshift mutation, Mutation Updates, 03 medical and health sciences, Rare Diseases, congenital tufting enteropathy, Malabsorption Syndromes, medicine, Genetics, Humans, Gene, Genetic Association Studies, 030304 developmental biology, EPCAM, Molecular, Epithelial Cells, medicine.disease, Congenital tufting enteropathy, Colorectal Neoplasms, Hereditary Nonpolyposis, Hereditary Nonpolyposis, MSH2, Mutation, Diarrhea, Infantile, Cancer research, RNA Splice Sites, Missense
Abstract: The epithelial cell adhesion molecule gene (EPCAM, previously known as TACSTD1 or TROP1) encodes a membrane‐bound protein that is localized to the basolateral membrane of epithelial cells and is overexpressed in some tumors. Biallelic mutations in EPCAM cause congenital tufting enteropathy (CTE), which is a rare chronic diarrheal disorder presenting in infancy. Monoallelic deletions of the 3′ end of EPCAM that silence the downstream gene, MSH2, cause a form of Lynch syndrome, which is a cancer predisposition syndrome associated with loss of DNA mismatch repair. Here, we report 13 novel EPCAM mutations from 17 CTE patients from two separate centers, review EPCAM mutations associated with CTE and Lynch syndrome, and structurally model pathogenic missense mutations. Statistical analyses indicate that the c.499dupC (previously reported as c.498insC) frameshift mutation was associated with more severe treatment regimens and greater mortality in CTE, whereas the c.556‐14A>G and c.491+1G>A splice site mutations were not correlated with treatments or outcomes significantly different than random simulation. These findings suggest that genotype–phenotype correlations may be useful in contributing to management decisions of CTE patients. Depending on the type and nature of EPCAM mutation, one of two unrelated diseases may occur, CTE or Lynch syndrome., Mutations in the epithelial cell adhesion molecule gene (EPCAM) can result in one of two unrelated diseases, congenital tufting enteropathy or Lynch Syndrome depending on the type and nature of the mutation. We report 13 novel EPCAM mutations from 17 CTE patients, review EPCAM mutations associated with CTE and Lynch syndrome, and structurally model pathogenic mutations. Statistical analyses to evaluate genotype‐phenotype correlations indicate that the c.499dupC frameshift mutation is associated with more severe treatment regimens and greater mortality in CTE.
Published: 2018

30. The evolving therapeutic landscape of genetic skeletal disorders

Author: Trevor Cole and Ataf Sabir
Subjects: Male, 0301 basic medicine, Dysplasia, lcsh:Medicine, Review, Disease, Palovarotene, Bioinformatics, Personalised, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Genetic, medicine, Animals, Humans, Pharmacology (medical), Bone, Genetics (clinical), business.industry, lcsh:R, Targeted, Skeletal, General Medicine, Osteogenesis Imperfecta, medicine.disease, Human genetics, Clinical trial, Drug repositioning, Hereditary, 030104 developmental biology, Myositis Ossificans, Rare, Drug development, Osteogenesis imperfecta, Osteopetrosis, 030220 oncology & carcinogenesis, Fibrodysplasia ossificans progressiva, Female, Therapy, Bone Diseases, business
Abstract: Background Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment technologies however, are leading to unparalleled therapeutic advance. This review explores the evolving therapeutic landscape of genetic skeletal disorders (GSDs); the key conditions and there key differentials. Methods A retrospective literature based review was conducted in December 2018 using a systematic search strategy for relevant articles and trials in Pubmed and clinicaltrials.gov respectively. Over 140 articles and 80 trials were generated for review. Results Over 20 personalised therapies are discussed in addition to several novel disease modifying treatments in over 25 GSDs. Treatments discussed are at different stages from preclinical studies to clinical trials and approved drugs, including; Burosumab for X-linked hypophosphatemia, Palovarotene for Hereditary Multiple Exostoses, Carbamazepine for Metaphyseal Chondrodysplasia (Schmid type), Lithium carbonate and anti-sclerostin therapy for Osteoporosis Pseudoglioma syndrome and novel therapies for Osteopetrosis. We also discuss therapeutic advances in Achondroplasia, Osteogenesis Imperfecta (OI), Hypophosphotasia (HPP), Fibrodysplasia Ossificans Progressiva, and RNA silencing therapies in preclinical studies for OI and HPP. Discussion It is an exciting time for GSD therapies despite the challenges of drug development in rare diseases. In discussing emerging therapies, we explore novel approaches to drug development from drug repurposing to in-utero stem cell transplants. We highlight the improved understanding of bone pathophysiology, genetic pathways and challenges of developing gene therapies for GSDs.
Published: 2019

31. Further delineation of Malan syndrome

Author: Ann Sophie Kaiser, Fowzan S. Alkuraya, Trevor Cole, Paul A. Mulder, Pablo Lapunzina, Inge B. Mathijssen, Jan Liebelt, Claire G. Salter, Pierre Sarda, Jill A. Fahrner, Manuela Priolo, Dorothee Neubauer, Nursel Elcioglu, Denny Schanze, Katrin Tatton-Brown, Sarah F. Smithson, Jair Tenorio, Thomas E. Neumann, Charles Shaw-Smith, Letizia Pintomalli, Shane McKee, Emilia K. Bijlsma, Sally J. Davies, Sue Price, Rajesh V. Thakker, Noelia García González, Rita Valdez, Sally Ann Lynch, Nataliya Di Donato, Arie van Haeringen, Astrid S. Plomp, Inés Hernández Acero, Ilka Huber, Marcela Zollino, Laura Bernardini, Raoul C.M. Hennekam, Martin Zenker, Mohnish Suri, Mabel Segovia, Johanna M. van Hagen, Ghayda Mirzaa, Leonie A. Menke, Kreepa Kooblall, Arveen Kamath, Christine Coubes, I. Dapia, Corrado Mammì, Alison Foster, Tara Montgomery, Pedro Arias, Fernando Santos-Simarro, Maria Iascone, Maria Antonietta Pisanti, Saskia M. Maas, ANS - Cellular & Molecular Mechanisms, Graduate School, ARD - Amsterdam Reproduction and Development, Human Genetics, Paediatric Genetics, General Paediatrics, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), Human genetics, and Pediatric surgery
Subjects: 0301 basic medicine, Male, Pediatrics, Developmental Disabilities, phenotype-genotype, Craniofacial Abnormalities, Epilepsy, Marshall–Smith syndrome, Septo-Optic Dysplasia, Intellectual disability, Child, Genetics (clinical), Research Articles, biology, Sotos syndrome, Exons, NFIX, Child, Preschool, Female, medicine.symptom, Chromosome Deletion, Hand Deformities, Congenital, Research Article, Adult, medicine.medical_specialty, Prominent forehead, phenotype‐genotype, Adolescent, phenotype, Mutation, Missense, 03 medical and health sciences, Young Adult, Intellectual Disability, Genetics, medicine, Congenital Hypothyroidism, Humans, Abnormalities, Multiple, Malan syndrome, Weaver syndrome, Bone Diseases, Developmental, Macrocephaly, medicine.disease, Marshall-Smith syndrome, Megalencephaly, NFI Transcription Factors, 030104 developmental biology, Marshall‐Smith syndrome, biology.protein
Abstract: Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only. This article is protected by copyright.
Published: 2018

32. Patient understanding of genetic information influences reproductive decision making in retinoblastoma

Author: Zerrin Onadim, Allen Foster, Trevor Cole, Mandeep S. Sagoo, L. Burgess, S. Carless, J. Hungerford, M.A. Reddy, Manoj Parulekar, V. Bowyer, Helen Jenkinson, L. Boyes, E. Rosser, and John R Ainsworth
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, medicine.diagnostic_test, Retinoblastoma, Offspring, business.industry, Audit, medicine.disease, Unilateral disease, eye diseases, Transition Care, 03 medical and health sciences, 030104 developmental biology, Genetics, medicine, Reproductive decision, Risk assessment, business, Genetics (clinical), Genetic testing
Abstract: Retinoblastoma is the most common malignant tumour of the eye in childhood, with nearly all bilateral tumours and around 17-18% of unilateral tumours due to an oncogenic mutation in the RB1 gene in the germline. Genetic testing in all cases enables accurate risk assessment and optimal clinical management for the affected individual, siblings, and future offspring. We carried out the first UK-wide audit of understanding of genetic testing in individuals with retinoblastoma. A total of 292 individuals aged 16-45 years were included. Patients with bilateral disease were significantly more likely to understand the implications of retinoblastoma for siblings and children. There was a significant association between not knowing the results of genetic testing or not understanding the implications and not having children, particularly in women. Surprisingly, this was also true for individuals treated for unilateral disease with a low risk of retinoblastoma for their offspring. We are concerned that individuals may be making life choices based on insufficient information regarding risks of retinoblastoma and reproductive options. We suggest that improvement in transition care is needed to enable individuals to make informed reproductive decisions and to ensure optimal care for children born at risk of retinoblastoma.
Published: 2017

33. Non-invasive prenatal diagnosis of spinal muscular atrophy by relative haplotype dosage

Author: Stephanie Allen, Michael J. Griffiths, Trevor Cole, Samuel Clokie, Julie Hewitt, Fiona Macdonald, Benjamin Bowns, Siobhan Cleary, Denise Williams, Samantha Court, and Michael Parks
Subjects: 0301 basic medicine, Proband, Male, Heterozygote, Prenatal diagnosis, SMN1, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Sensitivity and Specificity, Article, Muscular Atrophy, Spinal, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Prenatal Diagnosis, Genetics, medicine, Humans, Genetic Testing, Allele, Genetics (clinical), 030219 obstetrics & reproductive medicine, Massive parallel sequencing, Haplotype, Spinal muscular atrophy, SMA, medicine.disease, Survival of Motor Neuron 1 Protein, 3. Good health, Pedigree, 030104 developmental biology, Haplotypes, Case-Control Studies, Female
Abstract: Although technically possible, few clinical laboratories across the world have implemented non-invasive prenatal diagnosis (NIPD) for selected single-gene disorders, mostly owing to the elevated costs incurred. Having previously proven that NIPD for X-linked disorders can be feasibly implemented in clinical practice, we have now developed a test for the NIPD of an autosomal-recessive disorder, spinal muscular atrophy (SMA). Cell-free DNA was extracted from maternal blood and prepared for massively parallel sequencing on an Illumina MiSeq by targeted capture enrichment of single-nucleotide polymorphisms across a 6 Mb genomic window on chromosome 5 containing the SMN1 gene. Maternal, paternal and proband DNA samples were also tested for haplotyping purposes. Sequencing data was analysed by relative haplotype dosage (RHDO). Six pregnant SMA carriers and 10 healthy pregnant donors were recruited through the NIPSIGEN study. Inheritance of the maternally and paternally derived alleles of the affected SMN1 gene was determined in the foetus by RHDO analysis for autosomal-recessive disorders. DNA from the proband (for SMA carriers) or an invasively obtained foetal sample (for healthy pregnant donors) was used to identify the maternal and paternal reference haplotypes associated with the affected SMN1 gene. Results for all patients correlated with known outcomes and showed a testing specificity and sensitivity of 100%. On top of showing high accuracy and reliability throughout the stages of validation, our novel test for NIPD of SMA is also affordable and viable for implementation into clinical service.
Published: 2017

34. The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients

Author: Silvia Maitz, Elisa Rahikkala, Wayne Lam, Pedro A. Sanchez-Lara, Katherine Lachlan, Melissa Lees, Katherine L. Nathanson, Chey Loveday, Lionel Van Maldergem, Shane McKee, Dragana Josifova, Sally Ann Lynch, Katrina Tatton-Brown, Michael Parker, Ana Beleza-Meireles, Andrew G. L. Douglas, Sarina G. Kant, Philip J. Ostrowski, Tyler Mark Pierson, Yvonne Hilhorst-Hofstee, Sofia Douzgou, Kay Metcalfe, Marta Bertoli, Charlotte W. Ockeloen, Usha Kini, Diana Johnson, John Dean, Alice Spano, Trevor Cole, Alison Foster, Jennifer Hague, John M. Graham, Ian O. Ellis, Anna Zachariou, and Mariëtte J.V. Hoffer
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Scoliosis, macrocephaly, Young Adult, CHD8, Intellectual disability, Genetics, medicine, Humans, Child, overgrowth, Genetics (clinical), Growth Disorders, business.industry, Macrocephaly, Infant, Syndrome, medicine.disease, Cadherins, Umbilical hernia, Neonatal hypotonia, Phenotype, intellectual disability, Overgrowth syndrome, Child, Preschool, Autism, Female, Differential diagnosis, medicine.symptom, business, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract: Item does not contain fulltext CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference >/=2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (
Published: 2019

35. Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes

Author: Inge B. Mathijssen, Claire G. Salter, J M van Hagen, Tara Montgomery, Manuela Priolo, T. E. Neumann, Charles Shaw-Smith, I. H. Acero, Raoul C.M. Hennekam, L. Pintomalli, Fernando Santos-Simarro, Christine Coubes, Maria Iascone, Leonie A. Menke, Nursel Elcioglu, M. Zollino, Ghayda M. Mirzaa, Shane McKee, Rajesh V. Thakker, S. Piening, I. Dapia, C. Mammì, Arveen Kamath, Jair Tenorio, Emilia K. Bijlsma, Pierre Sarda, W. W. Dunn, Denny Schanze, Paul A. Mulder, Pablo Lapunzina, Martin Zenker, A. van Haeringen, Laura Bernardini, Jan Liebelt, N. Di Donato, Dorothee Neubauer, Jill A. Fahrner, Alison Foster, Sally Ann Lynch, Sue Price, A. M. Landlust, Sally J. Davies, N. G. González, I. Huber, Rita Valdez, I. D. C. van Balkom, Maria Antonietta Pisanti, Saskia M. Maas, Sarah F. Smithson, Pedro Arias, Mohnish Suri, Mabel Segovia, Kreepa Kooblall, Katrina Tatton-Brown, Trevor Cole, A. S. Plomp, Ann Sophie Kaiser, Fowzan S. Alkuraya, Pediatric surgery, Human genetics, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), Mulder, P. A., van Balkom, I. D. C., Landlust, A. M., Priolo, M., Menke, L. A., Acero, I. H., Alkuraya, F. S., Arias, P., Bernardini, L., Bijlsma, E. K., Cole, T., Coubes, C., Dapia, I., Davies, S., Di Donato, N., Elcioglu, N. H., Fahrner, J. A., Foster, A., Gonzalez, N. G., Huber, I., Iascone, M., Kaiser, A. -S., Kamath, A., Kooblall, K., Lapunzina, P., Liebelt, J., Lynch, S. A., Maas, S. M., Mammi, C., Mathijssen, I. B., McKee, S., Mirzaa, G. M., Montgomery, T., Neubauer, D., Neumann, T. E., Pintomalli, L., Pisanti, M. A., Plomp, A. S., Price, S., Salter, C., Santos-Simarro, F., Sarda, P., Schanze, D., Segovia, M., Shaw-Smith, C., Smithson, S., Suri, M., Tatton-Brown, K., Tenorio, J., Thakker, R. V., Valdez, R. M., Van Haeringen, A., Van Hagen, J. M., Zenker, M., Zollino, M., Dunn, W. W., Piening, S., Hennekam, R. C., Graduate School, ANS - Cellular & Molecular Mechanisms, General Paediatrics, ARD - Amsterdam Reproduction and Development, and Human Genetics
Subjects: cognition, Male, 030506 rehabilitation, Marshall–Smith syndrome, medicine.medical_treatment, CHILDREN, Comorbidity, Settore MED/03 - GENETICA MEDICA, Craniofacial Abnormalities, Quality of life, Septo-Optic Dysplasia, Intellectual disability, Adaptation, Psychological, sensory processing, Child, Netherlands, biology, Mental Disorders, 05 social sciences, Rehabilitation, Cognition, SOTOS-LIKE, Syndrome, NFIX, Psychiatry and Mental health, Phenotype, Neurology, adaptive behaviour, Child, Preschool, NFIX variants, Female, 0305 other medical science, Psychology, 050104 developmental & child psychology, Clinical psychology, Adult, Sensory processing, Adolescent, Challenging behaviour, NFIXvariants, Context (language use), AUTISTIC DISORDER, Speech Disorders, Article, 03 medical and health sciences, Young Adult, Arts and Humanities (miscellaneous), Intellectual Disability, medicine, Humans, 0501 psychology and cognitive sciences, Abnormalities, Multiple, Malan syndrome, Bone Diseases, Developmental, ADULTS, medicine.disease, Marshall-Smith syndrome, Cross-Sectional Studies, biology.protein, PATTERNS, Neurology (clinical), Follow-Up Studies
Abstract: BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.
Published: 2019

36. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author: Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Institut de Génétique et Développement de Rennes (IGDR), 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 ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), 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 ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)
Subjects: 0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
Published: 2019

37. Initial Validation of IBD KNOW-IT: Measuring Patient and Caregiver Knowledge of a Child's Disease and Treatment Regimen

Author: Allison Gordy, Vincent S. Staggs, Michele H Maddux, Trevor Cole, and Corey Schurman
Subjects: Male, 050103 clinical psychology, Adolescent, Psychometrics, Disease, 03 medical and health sciences, 0302 clinical medicine, Surveys and Questionnaires, Humans, 0501 psychology and cognitive sciences, 030212 general & internal medicine, Child, Self-management, Treatment regimen, Self-Management, 05 social sciences, Reproducibility of Results, Disease monitoring, Inflammatory Bowel Diseases, Clinical Psychology, Health psychology, Medication regimen, Knowledge, Convergent validity, Caregivers, Female, Psychology, Factor Analysis, Statistical, Dyad, Clinical psychology
Abstract: The present study describes the development and initial validation of a newly developed measure of child and caregiver knowledge of the child's own IBD and treatment, called IBD KNOW-IT. One hundred and fifty-five children and their caregivers completed the IBD KNOW-IT as well as a scale designed to compare each dyad's perceived knowledge to their actual knowledge. Initial psychometric evaluation of IBD KNOW-IT was completed by conducting factor analysis and determining internal consistency, convergent validity, and associations with demographic and medical characteristics. Results supported the validity of a 12-item measure with 4 subscales including Symptoms, Medication Regimen, Disease Monitoring, and Medical Team. Support for the internal consistency of IBD KNOW-IT was obtained. Evidence of validity was demonstrated by significant correlations between child and caregiver scales, and high congruence between perceived and actual knowledge across all subscales. The reliability of the measure was demonstrated by good internal consistency and test-retest reliability. Preliminary psychometric evaluation suggests that IBD KNOW-IT is reliable and valid.
Published: 2019

38. Identification of new Wilms tumour predisposition genes: an exome sequencing study

Author: Shazia, Mahamdallie, Shawn, Yost, Emma, Poyastro-Pearson, Esty, Holt, Anna, Zachariou, Sheila, Seal, Anna, Elliott, Matthew, Clarke, Margaret, Warren-Perry, Sandra, Hanks, John, Anderson, Simon, Bomken, Trevor, Cole, Roula, Farah, Rhoikos, Furtwaengler, Adam, Glaser, Richard, Grundy, James, Hayden, Steve, Lowis, Frédéric, Millot, James, Nicholson, Milind, Ronghe, Jane, Skeen, Denise, Williams, Daniel, Yeomanson, Elise, Ruark, and Nazneen, Rahman
Subjects: Adult, Genetic Markers, Male, Jumonji Domain-Containing Histone Demethylases, F-Box-WD Repeat-Containing Protein 7, Genes, Wilms Tumor, Adolescent, Middle Aged, Tripartite Motif-Containing Protein 28, Prognosis, Wilms Tumor, United Kingdom, Article, Kidney Neoplasms, Young Adult, Child, Preschool, Mutation, Exome Sequencing, Humans, Female, Genetic Predisposition to Disease, Exome, Child
Abstract: BACKGROUND: Wilms tumour is the most common childhood renal cancer and is genetically heterogeneous. While several Wilms tumour predisposition genes have been identified, there is strong evidence that further predisposition genes are likely to exist. Our study aim was to identify new predisposition genes for Wilms tumour. METHODS: In this exome sequencing study, we analysed lymphocyte DNA from 890 individuals with Wilms tumour, including 91 affected individuals from 49 familial Wilms tumour pedigrees. We used the protein-truncating variant prioritisation method to prioritise potential disease-associated genes for further assessment. We evaluated new predisposition genes in exome sequencing data that we generated in 334 individuals with 27 other childhood cancers and in exome data from The Cancer Genome Atlas obtained from 7632 individuals with 28 adult cancers. FINDINGS: We identified constitutional cancer-predisposing mutations in 33 individuals with childhood cancer. The three identified genes with the strongest signal in the protein-truncating variant prioritisation analyses were TRIM28, FBXW7, and NYNRIN. 21 of 33 individuals had a mutation in TRIM28; there was a strong parent-of-origin effect, with all ten inherited mutations being maternally transmitted (p=0·00098). We also found a strong association with the rare epithelial subtype of Wilms tumour, with 14 of 16 tumours being epithelial or epithelial predominant. There were no TRIM28 mutations in individuals with other childhood or adult cancers. We identified truncating FBXW7 mutations in four individuals with Wilms tumour and a de-novo non-synonymous FBXW7 mutation in a child with a rhabdoid tumour. Biallelic truncating mutations in NYNRIN were identified in three individuals with Wilms tumour, which is highly unlikely to have occurred by chance (p
Published: 2019

39. A MESOZOIC RECORD OF FLUVIAL RESPONSE TO CLIMATIC AND TECTONIC PERTURBATIONS, ORDOS BASIN, NORTH-CENTRAL CHINA

Author: Mark A. Torres, Yuliang Duan, Trevor Cole, Chenliang Wu, and Jeffrey A. Nittrouer
Subjects: Tectonics, Paleontology, North central, Fluvial, Mesozoic, Structural basin, China, Geology
Published: 2019

40. Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing

Author: Karyn Megy, Nicholas Gleadall, Christopher E. French, Ricardo Garcia Branco, Marie Erwood, Topun Austin, Olga Shamardina, Willem H. Ouwehand, Helen Dolling, F Lucy Raymond, Alba Sanchis-Juan, Luca Stefanucci, Keren J. Carss, Jonathan Stephens, Eleanor Dewhurst, Trevor Cole, Christopher J. Penkett, Isabelle Delon, Detelina Grozeva, Kathleen Stirrups, Andrew R. Webster, Gavin Arno, Stephens, Jonathan [0000-0003-2020-9330], French, Courtney [0000-0001-7620-1544], Shamardina, Olga [0000-0003-4994-2157], Johnson, Kathleen [0000-0002-6823-3252], Dolling, Helen [0000-0001-6279-3622], Stefanucci, Luca [0000-0002-4352-1151], Austin, Topun [0000-0002-8428-8624], Ouwehand, Willem [0000-0002-7744-1790], Raymond, Lucy [0000-0003-2652-3355], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Nanopore, Male, lcsh:QH426-470, Systems biology, CDKL5, lcsh:Medicine, Cell Cycle Proteins, Heterogeneous-Nuclear Ribonucleoprotein U, Biology, Protein Serine-Threonine Kinases, Genome sequencing, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Genetics, CEP78, Humans, Genetic Predisposition to Disease, Allele, Molecular Biology, Genetics (clinical), Genome, Human, Research, Breakpoint, lcsh:R, Complex structural variant, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Human genetics, ARID1B, DNA-Binding Proteins, lcsh:Genetics, 030104 developmental biology, HNRNPU, Genomic Structural Variation, Mutation, Next-generation sequencing, Molecular Medicine, Identification (biology), Female, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Background Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation. Methods We performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case. Results We identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements. Conclusions Our results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation. Electronic supplementary material The online version of this article (10.1186/s13073-018-0606-6) contains supplementary material, which is available to authorized users.
Published: 2018

41. The Impact of Cell-Free DNA Analysis on the Management of Retinoblastoma

Author: Trevor Cole, Helen Jenkinson, and Amy Gerrish
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Somatic cell, Prenatal diagnosis, Review, lcsh:RC254-282, Genetic analysis, retinoblastoma, cell-free DNA, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Liquid biopsy, Potential impact, liquid biopsy, Retinoblastoma, business.industry, Cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, eye diseases, 030104 developmental biology, Cell-free fetal DNA, noninvasive prenatal diagnosis, 030221 ophthalmology & optometry, business
Abstract: Simple Summary Retinoblastoma is a childhood eye cancer caused almost entirely by defects in a gene known as RB1. Other genetic changes within the tumour are also thought to affect the progression of disease. Until recently, tumour DNA could only be analysed if the eye was removed as part of patient treatment. However, recent research has shown that the analysis of a particular type of DNA, known as cell-free DNA, within the eye fluid or blood of patients, can be used to detect changes in the RB1 gene or other parts of the genome within a retinoblastoma tumour. The analysis of cell-free DNA in the blood of pregnant women can also be used to detect whether the unborn baby will be affected with retinoblastoma. In this review, we summarise these studies and discuss the potential impact of cell-free DNA analysis on retinoblastoma patient management in the future. Abstract Retinoblastoma is a childhood eye cancer, mainly caused by mutations in the RB1 gene, which can be somatic or constitutional. Unlike many other cancers, tumour biopsies are not performed due to the risk of tumour dissemination. As a result, until recently, somatic genetic analysis was only possible if an affected eye was removed as part of a treatment. Several recent proof of principle studies have demonstrated that the analysis of tumour-derived cell-free DNA, either obtained from ocular fluid or blood plasma, has the potential to advance the diagnosis and influence the prognosis of retinoblastoma patients. It has been shown that a confirmed diagnosis is possible in retinoblastoma patients undergoing conservative treatment. In vivo genetic analysis of retinoblastoma tumours is also now possible, allowing the potential identification of secondary genetic events as prognostic biomarkers. In addition, noninvasive prenatal diagnosis in children at risk of inheriting retinoblastoma has been developed. Here, we review the current literature and discuss the potential impact of cell-free DNA analysis on both the diagnosis and treatment of retinoblastoma patients and their families.
Published: 2021

42. Non-invasive prenatal diagnosis of Duchenne and Becker muscular dystrophies by relative haplotype dosage

Author: Fiona Macdonald, Samantha Court, Michael Parks, Julie Hewitt, Michael J. Griffiths, Trevor Cole, Siobhan Cleary, Denise Williams, Samuel Clokie, and Stephanie Allen
Subjects: musculoskeletal diseases, 0301 basic medicine, Proband, congenital, hereditary, and neonatal diseases and abnormalities, Pathology, medicine.medical_specialty, 030219 obstetrics & reproductive medicine, Massive parallel sequencing, medicine.diagnostic_test, Obstetrics, Maternal Serum Screening Tests, business.industry, Haplotype, Obstetrics and Gynecology, Chorionic villus sampling, Single-nucleotide polymorphism, Prenatal diagnosis, 030105 genetics & heredity, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine, business, Genetics (clinical), Genetic testing
Abstract: Objective Development of an accurate and affordable test for the non-invasive prenatal diagnosis of Duchenne and Becker muscular dystrophies (DMD/BMD) to implement in clinical practice. Method Cell-free DNA was extracted from maternal blood and prepared for massively parallel sequencing on an Illumina MiSeq by targeted capture enrichment of single nucleotide polymorphisms (SNPs) across the dystrophin gene on chromosome X. Sequencing data were analysed by relative haplotype dosage. Results Seven healthy pregnant donors and two pregnant DMD carriers all bearing a male fetus were recruited through the non-invasive prenatal diagnosis for single gene disorders study. Non-invasive prenatal diagnosis testing was conducted by relative haplotype dosage analysis for X-linked disorders where the genomic DNA from the chorionic villus sampling (for healthy pregnant donors) or from the proband (for pregnant DMD carriers) was used to identify the reference haplotype. Results for all patients showed a test accuracy of 100%, when the calculated fetal fraction was >4% and correlated with known outcomes. A recombination event was also detected in a DMD patient. Conclusion Our new test for NIPD of DMD/BMD has been shown to be accurate and reliable during initial stages of validation. It is also feasible for implementation into clinical service. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
Published: 2016

43. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author: Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care
Subjects: 0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: © 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.
Published: 2018

44. Where Are They Now? Review of patients diagnosed with Disorders of Sex Development since 1988

Author: Stephanie Allen, Graham A Fews, Zainaba Mohamed, Jeremy Kirk, Jan Idkowiak, Helena Gleeson, Nils Krone, Trevor Cole, Pallavi Latthe, Kimiya Bagheri, and Hina Kanani
Subjects: Pediatrics, medicine.medical_specialty, business.industry, medicine, Disorders of sex development, business, medicine.disease
Published: 2018

45. Management of osteogenesis imperfecta in adulthood - a single centre experience

Author: Trevor Cole, Zaki Hassan-Smith, John Ayuk, Shakib Khan, Shujah Dar, Naveed Khalily, Neil Gittoes, and Vicky Kamwa
Subjects: Pediatrics, medicine.medical_specialty, Single centre, business.industry, Osteogenesis imperfecta, medicine, business, medicine.disease
Published: 2018

46. Pitfalls in the diagnosis of an infant with 46,XX DSD with Congenital Adrenal Hyperplasia due to Cytochrome P450 Oxidoreductase deficiency - the value of simultaneous genetic analysis to the diagnosis in DSD

Author: Nils Krone, Trevor Cole, Harish Chandran, Stephanie Allen, Jeremy Kirk, Liam McCarthy, Jan Idkowiak, and Zainaba Mohamed
Subjects: medicine.medical_specialty, Endocrinology, business.industry, Internal medicine, medicine, Congenital adrenal hyperplasia, medicine.disease, business, Genetic analysis, Value (mathematics), Cytochrome P450 Oxidoreductase Deficiency
Published: 2018

47. Non-invasive diagnosis of retinoblastoma using cell-free DNA from aqueous humour

Author: Carol Hitchcott, John R Ainsworth, Trevor Cole, Manoj Parulekar, Maureen McCalla, Isabel Colmenero, Stephanie Allen, Amy Gerrish, Edward Stone, Samuel Clokie, and Helen Jenkinson
Subjects: Mutation, business.industry, Retinoblastoma, Aqueous humour, Somatic cell, medicine.disease, Malignancy, medicine.disease_cause, eye diseases, Sensory Systems, Germline, 3. Good health, Miscellaneous, 03 medical and health sciences, Cellular and Molecular Neuroscience, Ophthalmology, 0302 clinical medicine, Germline mutation, Cell-free fetal DNA, 030220 oncology & carcinogenesis, 030221 ophthalmology & optometry, Cancer research, Medicine, business
Abstract: Retinoblastoma is the most common eye malignancy in childhood caused by mutations in the RB1 gene. Both alleles of the RB1 gene must be mutated for tumour development. The initial RB1 mutation may be constitutional germline or somatic (originating in one retinal cell only). Distinguishing between these alternative mechanisms is crucial, with wider implications for management of the patient and family members. Bilateral retinoblastoma is nearly always due to a constitutional mutation; however, approximately 15% of unilateral cases also carry a germline mutation, and identifying these cases is important. This can be achieved by identifying both mutation types in tumour tissue and excluding their presence in blood. Modern eye-saving chemotherapy treatment (systemic, intra-arterial and intravitreal) has resulted in fewer enucleations. As a result, tumour tissue required to identify sporadic RB1 mutation(s) is not always available. Modern intravitreal chemotherapeutic techniques for retinoblastoma involve aspiration of aqueous humour (AH), providing a novel sample source for analysis. By analysing cell-free DNA present in the AH fluid of eyes affected with retinoblastoma, we have developed a screening test capable of detecting somatic RB1 mutations that is comparable to current tests on enucleated tumour tissue. The results obtained with fluid from enucleated eyes were concordant with tumour tissue in all 10 cases analysed. In addition, AH analysis from two patients undergoing intravitreal chemotherapy successfully identified somatic variants in both cases. Our findings suggest that AH fluid is a promising source of tumour-derived DNA in retinoblastoma for analysis.
Published: 2018

48. Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement

Author: Christian P. Kratz, Le Bouc Y, Ibrahim A, Jennifer M. Kalish, Tatton-Brown, Frédéric Brioude, Sylvie Rossignol, Jair Tenorio, Kilby, Giovanni Battista Ferrero, Irène Netchine, De Pellegrin M, Raoul C.M. Hennekam, Silvia Russo, Fiona Macdonald, Trevor Cole, Eamonn R. Maher, Mackay Djg, Karen Grønskov, Edmund J. Ladusans, Khalid Hussain, Licia Peruzzi, Saskia M. Maas, Andrea Riccio, Susanne E Boonen, Monica Bertoletti, Pablo Lapunzina, Zeynep Tümer, oze C, Jet Bliek, Alison Foster, Chiara Tortora, Thomas Eggermann, Guido Cocchi, Caroleen Shipster, Małgorzata Krajewska-Walasek, Dirk Prawitt, Robert Baker, Katrin Õunap, Alessandro Mussa, Agata Skórka, Human Genetics, Paediatric Genetics, APH - Quality of Care, ARD - Amsterdam Reproduction and Development, Maher, Eamonn [0000-0002-6226-6918], and Apollo - University of Cambridge Repository
Subjects: medicine.medical_specialty, Beckwith-Wiedemann Syndrome, Consensus, DNA Copy Number Variations, Reproductive Techniques, Assisted, Statement (logic), Beckwith–Wiedemann syndrome, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Prenatal Diagnosis, Humans, Medicine, 030304 developmental biology, 0303 health sciences, business.industry, Expert consensus, DNA Methylation, Neoplasms, Germ Cell and Embryonal, medicine.disease, 3. Good health, Molecular Diagnostic Techniques, 030220 oncology & carcinogenesis, Family medicine, business
Abstract: Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.
Published: 2018

49. Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: An international consensus statement

Author: Christian P. Kratz, Monica Bertoletti, Jet Bliek, Khalid Hussain, Thomas Eggermann, Trevor Cole, Pablo Lapunzina, Edmund J. Ladusans, Fiona Macdonald, Dirk Prawitt, Guido Cocchi, Giovanni Battista Ferrero, Jennifer M. Kalish, Katrina Tatton-Brown, Katrin Õunap, Sylvie Rossignol, Karen Grønskov, Małgorzata Krajewska-Walasek, Alison Foster, Maurizio De Pellegrin, Irène Netchine, Saskia M. Maas, Robert Baker, Abdulla Ibrahim, Frédéric Brioude, Alessandro Mussa, Zeynep Tümer, Susanne E Boonen, Chiara Tortora, Licia Peruzzi, Agata Skórka, Deborah J G Mackay, Raoul C.M. Hennekam, Jair Tenorio, Yves Le Bouc, Mark D. Kilby, Carole Coze, Silvia Russo, Caroleen Shipster, Andrea Riccio, Eamonn R. Maher, Brioude, Frédéric, Kalish, Jennifer M, Mussa, Alessandro, Foster, Alison C, Bliek, Jet, Ferrero, Giovanni Battista, Boonen, Susanne E, Cole, Trevor, Baker, Robert, Bertoletti, Monica, Cocchi, Guido, Coze, Carole, De Pellegrin, Maurizio, Hussain, Khalid, Ibrahim, Abdulla, Kilby, Mark D, Krajewska-Walasek, Malgorzata, Kratz, Christian P, Ladusans, Edmund J, Lapunzina, Pablo, Le Bouc, Yve, Maas, Saskia M, Macdonald, Fiona, Õunap, Katrin, Peruzzi, Licia, Rossignol, Sylvie, Russo, Silvia, Shipster, Caroleen, Skórka, Agata, Tatton-Brown, Katrina, Tenorio, Jair, Tortora, Chiara, Grønskov, Karen, Netchine, Irène, Hennekam, Raoul C, Prawitt, Dirk, Tümer, Zeynep, Eggermann, Thoma, Mackay, Deborah J. G, Riccio, Andrea, Maher, Eamonn R., Kalish, Jennifer M., Foster, Alison C., Boonen, Susanne E., Kilby, Mark D., Kratz, Christian P., Ladusans, Edmund J., Bouc, Yves Le, Maas, Saskia M., MacDonald, Fiona, Hennekam, Raoul C., Mackay, Deborah J.G., Maher, Eamonn [0000-0002-6226-6918], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Beckwith-Wiedemann Syndrome, Consensus, DNA Copy Number Variations, Reproductive Techniques, Assisted, Endocrinology, Diabetes and Metabolism, Library science, 32 Biomedical and Clinical Sciences, Translational research, 030105 genetics & heredity, Polymorphism, Single Nucleotide, Bildung, 03 medical and health sciences, Rare Diseases, Endocrinology, Prenatal Diagnosis, Humans, Medicine, media_common.cataloged_instance, Pediatric nephrology, Child growth, European union, 3202 Clinical Sciences, media_common, Pediatric, business.industry, European research, Expert consensus, DNA Methylation, Neoplasms, Germ Cell and Embryonal, National health service, 3. Good health, Molecular Diagnostic Techniques, business
Abstract: Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways. Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.
Published: 2018

50. Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders

Author: Víctor Faundes, William G. Newman, Laura Bernardini, Natalie Canham, Jill Clayton-Smith, Bruno Dallapiccola, Sally J. Davies, Michelle K. Demos, Amy Goldman, Harinder Gill, Rachel Horton, Bronwyn Kerr, Dhavendra Kumar, Anna Lehman, Shane McKee, Jenny Morton, Michael J. Parker, Julia Rankin, Lisa Robertson, I. Karen Temple, Siddharth Banka, Shelin Adam, Christèle du Souich, Alison M. Elliott, Jill Mwenifumbo, Tanya N. Nelson, Clara van Karnebeek, Jan M. Friedman, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, V.K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, and Matthew E. . Hurles
Subjects: 0301 basic medicine, ASH1L, Male, Methyltransferase, Adolescent, Histone lysine methylation, KMT5B, Developmental Disabilities, Haploinsufficiency, Biology, Compound heterozygosity, histone lysine methyltransferase, Chromatin remodeling, chromatin remodeling, 03 medical and health sciences, histone lysine demethylase, Report, Genetics, Humans, Child, Genetics (clinical), Regulation of gene expression, Histone Demethylases, Developmental disorders, KMT2C, KMT2B, Histone-Lysine N-Methyltransferase, 030104 developmental biology, Histone, Overgrowth syndrome, Child, Preschool, Mutation, biology.protein, KDM5B, Female
Abstract: Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.
Published: 2017

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