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1. The role of DEAD- and DExH-box RNA helicases in neurodevelopmental disorders

Author

Johannes Lederbauer, Sarada Das, Amelie Piton, Davor Lessel, and Hans-Jürgen Kreienkamp

Subjects
stress granules, P-bodies, miRNA, translation, R-loop, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Neurodevelopmental disorders (NDDs) represent a large group of disorders with an onset in the neonatal or early childhood period; NDDs include intellectual disability (ID), autism spectrum disorders (ASD), attention deficit hyperactivity disorders (ADHD), seizures, various motor disabilities and abnormal muscle tone. Among the many underlying Mendelian genetic causes for these conditions, genes coding for proteins involved in all aspects of the gene expression pathway, ranging from transcription, splicing, translation to the eventual RNA decay, feature rather prominently. Here we focus on two large families of RNA helicases (DEAD- and DExH-box helicases). Genetic variants in the coding genes for several helicases have recently been shown to be associated with NDD. We address genetic constraints for helicases, types of pathological variants which have been discovered and discuss the biological pathways in which the affected helicase proteins are involved.

Published
2024
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2. Genetic causal relationship between immune diseases and migraine: a Mendelian randomization study

Author

Guanglu Li, Shaojie Duan, International Headache Genetics Consortium (IHGC), Tao Zheng, Tiantian Zhu, Baoquan Qu, Lei Liu, Zunjing Liu, Verneri Anttila, Ville Artto, Andrea C Belin, Anna Bjornsdottir, Gyda Bjornsdottir, Dorret I Boomsma, Sigrid Børte, Mona A Chalmer, Daniel I Chasman, Bru Cormand, Ester Cuenca-Leon, George Davey-Smith, Irene de Boer, Martin Dichgans, Tonu Esko, Tobias Freilinger, Padhraig Gormley, Lyn R Griffiths, Eija Hämäläinen, Thomas F Hansen, Aster VE Harder, Heidi Hautakangas, Marjo Hiekkala, Maria G Hrafnsdottir, M. Arfan Ikram, Marjo-Riitta Järvelin, Risto Kajanne, Mikko Kallela, Jaakko Kaprio, Mari Kaunisto, Lisette JA Kogelman, Espen S Kristoffersen, Christian Kubisch, Mitja Kurki, Tobias Kurth, Lenore Launer, Terho Lehtimäki, Davor Lessel, Lannie Ligthart, Sigurdur H Magnusson, Rainer Malik, Bertram Müller-Myhsok, Carrie Northover, Dale R Nyholt, Jes Olesen, Aarno Palotie, Priit Palta, Linda M Pedersen, Nancy Pedersen, Matti Pirinen, Danielle Posthuma, Patricia Pozo-Rosich, Alice Pressman, Olli Raitakari, Caroline Ran, Gudrun R Sigurdardottir, Hreinn Stefansson, Kari Stefansson, Olafur A Sveinsson, Gisela M Terwindt, Thorgeir E Thorgeirsson, Arn MJM vanden Maagdenberg, Cornelia van Duijn, Maija Wessman, Bendik S Winsvold, and John-Anker Zwart.

Subjects
migraine, immune diseases, causal association, Mendelian randomization, genetic correlation, Immunologic diseases. Allergy, RC581-607
Abstract

BackgroundMigraine has an increased prevalence in several immune disorders, but genetic cause-effect relationships remain unclear. Mendelian randomization (MR) was used in this study to explore whether immune diseases are causally associated with migraine and its subtypes.MethodsWe conducted a two-sample bidirectional multivariate Mendelian randomization study. Single-nucleotide polymorphisms (SNP) for six immune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), allergic rhinitis (AR), asthma and psoriasis, were used as genetic instrumental variables. Summary statistics for migraine were obtained from 3 databases: the International Headache Genetics Consortium (IHGC), UK Biobank, and FinnGen study. MR analyses were performed per outcome database for each exposure and subsequently meta-analyzed. Reverse MR analysis was performed to determine whether migraine were risk factors for immune diseases. In addition, we conducted a genetic correlation to identify shared genetic variants for these two associations.ResultsNo significant causal relationship was found between immune diseases and migraine and its subtypes. These results were robust with a series of sensitivity analyses. Using the linkage disequilibrium score regression method (LDSC), we detected no genetic correlation between migraine and immune diseases.ConclusionThe evidence from our study does not support a causal relationship between immune diseases and migraine. The mechanisms underlying the frequent comorbidity of migraine and several immune diseases need to be further elucidated.

Published
2024
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3. Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysisResearch in context

Author

James Yarmolinsky, Jamie W. Robinson, Daniela Mariosa, Ville Karhunen, Jian Huang, Niki Dimou, Neil Murphy, Kimberley Burrows, Emmanouil Bouras, Karl Smith-Byrne, Sarah J. Lewis, Tessel E. Galesloot, Lambertus A. Kiemeney, Sita Vermeulen, Paul Martin, Demetrius Albanes, Lifang Hou, Polly A. Newcomb, Emily White, Alicja Wolk, Anna H. Wu, Loïc Le Marchand, Amanda I. Phipps, Daniel D. Buchanan, Sizheng Steven Zhao, Dipender Gill, Stephen J. Chanock, Mark P. Purdue, George Davey Smith, Paul Brennan, Karl-Heinz Herzig, Marjo-Riitta Järvelin, Chris I. Amos, Rayjean J. Hung, Abbas Dehghan, Mattias Johansson, Marc J. Gunter, Kostas K. Tsilidis, Richard M. Martin, Maria Teresa Landi, Victoria Stevens, Ying Wang, Demetrios Albanes, Neil Caporaso, Christopher I. Amos, Sanjay Shete, Heike Bickeböller, Angela Risch, Richard Houlston, Stephen Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, H-Erich Wichmann, David Christiani, Gadi Rennert, Susanne Arnold, John K. Field, Loic Le Marchand, Olle Melander, Hans Brunnström, Geoffrey Liu, Angeline Andrew, Hongbing Shen, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, M. Dawn Teare, Yun-Chul Hong, Jian-Min Yuan, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Rosalind A. Eeles, Christopher A. Haiman, Zsofia Kote-Jarai, Fredrick R. Schumacher, Sara Benlloch, Ali Amin Al Olama, Kenneth R. Muir, Sonja I. Berndt, David V. Conti, Fredrik Wiklund, Stephen Chanock, Catherine M. Tangen, Jyotsna Batra, Judith A. Clements, Henrik Grönberg, Nora Pashayan, Johanna Schleutker, Stephanie J. Weinstein, Catharine M.L. West, Lorelei A. Mucci, Géraldine Cancel-Tassin, Stella Koutros, Karina Dalsgaard Sørensen, Eli Marie Grindedal, David E. Neal, Freddie C. Hamdy, Jenny L. Donovan, Ruth C. Travis, Robert J. Hamilton, Sue Ann Ingles, Barry S. Rosenstein, Yong-Jie Lu, Graham G. Giles, Robert J. MacInnis, Adam S. Kibel, Ana Vega, Manolis Kogevinas, Kathryn L. Penney, Jong Y. Park, Janet L. Stanfrod, Cezary Cybulski, Børge G. Nordestgaard, Sune F. Nielsen, Hermann Brenner, Christiane Maier, Christopher J. Logothetis, Esther M. John, Manuel R. Teixeira, Susan L. Neuhausen, Kim De Ruyck, Azad Razack, Lisa F. Newcomb, Davor Lessel, Radka Kaneva, Nawaid Usmani, Frank Claessens, Paul A. Townsend, Jose Esteban Castelao, Monique J. Roobol, Florence Menegaux, Kay-Tee Khaw, Lisa Cannon-Albright, Hardev Pandha, Stephen N. Thibodeau, David J. Hunter, Peter Kraft, William J. Blot, and Elio Riboli

Subjects
Inflammation, Cancer, Mendelian randomization, Genetic epidemiology, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. Findings: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10–1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20–1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53–0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88–0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48–4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Interpretation: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. Funding: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).

Published
2024
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4. Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation

Author

Lina Merkens, Verena Sailer, Davor Lessel, Ella Janzen, Sarah Greimeier, Jutta Kirfel, Sven Perner, Klaus Pantel, Stefan Werner, and Gunhild von Amsberg

Subjects
Aggressive variant prostate cancer, Small cell prostate cancer, Neuroendocrine prostate cancer, Neuroendocrine transdifferentiation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Prostate cancer is a hormone-driven disease and its tumor cell growth highly relies on increased androgen receptor (AR) signaling. Therefore, targeted therapy directed against androgen synthesis or AR activation is broadly used and continually improved. However, a subset of patients eventually progresses to castration-resistant disease. To date, various mechanisms of resistance have been identified including the development of AR-independent aggressive variant prostate cancer based on neuroendocrine transdifferentiation (NED). Here, we review the highly complex processes contributing to NED. Genetic, epigenetic, transcriptional aberrations and posttranscriptional modifications are highlighted and the potential interplay of the different factors is discussed. Background Aggressive variant prostate cancer (AVPC) with traits of neuroendocrine differentiation emerges in a rising number of patients in recent years. Among others, advanced therapies targeting the androgen receptor axis have been considered causative for this development. Cell growth of AVPC often occurs completely independent of the androgen receptor signal transduction pathway and cells have mostly lost the typical cellular features of prostate adenocarcinoma. This complicates both diagnosis and treatment of this very aggressive disease. We believe that a deeper understanding of the complex molecular pathological mechanisms contributing to transdifferentiation will help to improve diagnostic procedures and develop effective treatment strategies. Indeed, in recent years, many scientists have made important contributions to unravel possible causes and mechanisms in the context of neuroendocrine transdifferentiation. However, the complexity of the diverse molecular pathways has not been captured completely, yet. This narrative review comprehensively highlights the individual steps of neuroendocrine transdifferentiation and makes an important contribution in bringing together the results found so far.

Published
2022
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5. Identification of 22 susceptibility loci associated with testicular germ cell tumors

Author

John Pluta, Louise C. Pyle, Kevin T. Nead, Rona Wilf, Mingyao Li, Nandita Mitra, Benita Weathers, Kurt D’Andrea, Kristian Almstrup, Lynn Anson-Cartwright, Javier Benitez, Christopher D. Brown, Stephen Chanock, Chu Chen, Victoria K. Cortessis, Alberto Ferlin, Carlo Foresta, Marija Gamulin, Jourik A. Gietema, Chiara Grasso, Mark H. Greene, Tom Grotmol, Robert J. Hamilton, Trine B. Haugen, Russ Hauser, Michelle A. T. Hildebrandt, Matthew E. Johnson, Robert Karlsson, Lambertus A. Kiemeney, Davor Lessel, Ragnhild A. Lothe, Jennifer T. Loud, Chey Loveday, Paloma Martin-Gimeno, Coby Meijer, Jérémie Nsengimana, David I. Quinn, Thorunn Rafnar, Shweta Ramdas, Lorenzo Richiardi, Rolf I. Skotheim, Kari Stefansson, Clare Turnbull, David J. Vaughn, Fredrik Wiklund, Xifeng Wu, Daphne Yang, Tongzhang Zheng, Andrew D. Wells, Struan F. A. Grant, Ewa Rajpert-De Meyts, Stephen M. Schwartz, D. Timothy Bishop, Katherine A. McGlynn, Peter A. Kanetsky, Katherine L. Nathanson, and The Testicular Cancer Consortium

Subjects
Science
Abstract

Testicular germ cell tumors are highly heritable, and the authors present the largest genome association study, identifying 22 novel loci, which account for a third of those identified to date. Implicated pathways include male germ cell development and differentiation, and chromosomal segregation.

Published
2021
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6. Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Ilaria Mannucci, Nghi D. P. Dang, Hannes Huber, Jaclyn B. Murry, Jeff Abramson, Thorsten Althoff, Siddharth Banka, Gareth Baynam, David Bearden, Ana Beleza-Meireles, Paul J. Benke, Siren Berland, Tatjana Bierhals, Frederic Bilan, Laurence A. Bindoff, Geir Julius Braathen, Øyvind L. Busk, Jirat Chenbhanich, Jonas Denecke, Luis F. Escobar, Caroline Estes, Julie Fleischer, Daniel Groepper, Charlotte A. Haaxma, Maja Hempel, Yolanda Holler-Managan, Gunnar Houge, Adam Jackson, Laura Kellogg, Boris Keren, Catherine Kiraly-Borri, Cornelia Kraus, Christian Kubisch, Gwenael Le Guyader, Ulf W. Ljungblad, Leslie Manace Brenman, Julian A. Martinez-Agosto, Matthew Might, David T. Miller, Kelly Q. Minks, Billur Moghaddam, Caroline Nava, Stanley F. Nelson, John M. Parant, Trine Prescott, Farrah Rajabi, Hanitra Randrianaivo, Simone F. Reiter, Janneke Schuurs-Hoeijmakers, Perry B. Shieh, Anne Slavotinek, Sarah Smithson, Alexander P. A. Stegmann, Kinga Tomczak, Kristian Tveten, Jun Wang, Jordan H. Whitlock, Christiane Zweier, Kirsty McWalter, Jane Juusola, Fabiola Quintero-Rivera, Utz Fischer, Nan Cher Yeo, Hans-Jürgen Kreienkamp, and Davor Lessel

Subjects
Medicine, Genetics, QH426-470
Abstract

Abstract Background We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. Methods Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. Results We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. Conclusions Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.

Published
2021
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7. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Author

Madelyn A. Gillentine, Tianyun Wang, Kendra Hoekzema, Jill Rosenfeld, Pengfei Liu, Hui Guo, Chang N. Kim, Bert B. A. De Vries, Lisenka E. L. M. Vissers, Magnus Nordenskjold, Malin Kvarnung, Anna Lindstrand, Ann Nordgren, Jozef Gecz, Maria Iascone, Anna Cereda, Agnese Scatigno, Silvia Maitz, Ginevra Zanni, Enrico Bertini, Christiane Zweier, Sarah Schuhmann, Antje Wiesener, Micah Pepper, Heena Panjwani, Erin Torti, Farida Abid, Irina Anselm, Siddharth Srivastava, Paldeep Atwal, Carlos A. Bacino, Gifty Bhat, Katherine Cobian, Lynne M. Bird, Jennifer Friedman, Meredith S. Wright, Bert Callewaert, Florence Petit, Sophie Mathieu, Alexandra Afenjar, Celenie K. Christensen, Kerry M. White, Orly Elpeleg, Itai Berger, Edward J. Espineli, Christina Fagerberg, Charlotte Brasch-Andersen, Lars Kjærsgaard Hansen, Timothy Feyma, Susan Hughes, Isabelle Thiffault, Bonnie Sullivan, Shuang Yan, Kory Keller, Boris Keren, Cyril Mignot, Frank Kooy, Marije Meuwissen, Alice Basinger, Mary Kukolich, Meredith Philips, Lucia Ortega, Margaret Drummond-Borg, Mathilde Lauridsen, Kristina Sorensen, Anna Lehman, CAUSES Study, Elena Lopez-Rangel, Paul Levy, Davor Lessel, Timothy Lotze, Suneeta Madan-Khetarpal, Jessica Sebastian, Jodie Vento, Divya Vats, L. Manace Benman, Shane Mckee, Ghayda M. Mirzaa, Candace Muss, John Pappas, Hilde Peeters, Corrado Romano, Maurizio Elia, Ornella Galesi, Marleen E. H. Simon, Koen L. I. van Gassen, Kara Simpson, Robert Stratton, Sabeen Syed, Julien Thevenon, Irene Valenzuela Palafoll, Antonio Vitobello, Marie Bournez, Laurence Faivre, Kun Xia, SPARK Consortium, Rachel K. Earl, Tomasz Nowakowski, Raphael A. Bernier, and Evan E. Eichler

Subjects
Neurodevelopmental disorders, hnRNPs, Cortex development, Gene families, Medicine, Genetics, QH426-470
Abstract

Abstract Background With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype–phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. Methods We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. Results We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188–221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. Conclusions Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Published
2021
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8. Germline AGO2 mutations impair RNA interference and human neurological development

Author

Davor Lessel, Daniela M. Zeitler, Margot R. F. Reijnders, Andriy Kazantsev, Fatemeh Hassani Nia, Alexander Bartholomäus, Victoria Martens, Astrid Bruckmann, Veronika Graus, Allyn McConkie-Rosell, Marie McDonald, Bernarda Lozic, Ee-Shien Tan, Erica Gerkes, Jessika Johannsen, Jonas Denecke, Aida Telegrafi, Evelien Zonneveld-Huijssoon, Henny H. Lemmink, Breana W. M. Cham, Tanja Kovacevic, Linda Ramsdell, Kimberly Foss, Diana Le Duc, Diana Mitter, Steffen Syrbe, Andreas Merkenschlager, Margje Sinnema, Bianca Panis, Joanna Lazier, Matthew Osmond, Taila Hartley, Jeremie Mortreux, Tiffany Busa, Chantal Missirian, Pankaj Prasun, Sabine Lüttgen, Ilaria Mannucci, Ivana Lessel, Claudia Schob, Stefan Kindler, John Pappas, Rachel Rabin, Marjolein Willemsen, Thatjana Gardeitchik, Katharina Löhner, Patrick Rump, Kerith-Rae Dias, Carey-Anne Evans, Peter Ian Andrews, Tony Roscioli, Han G. Brunner, Chieko Chijiwa, M. E. Suzanne Lewis, Rami Abou Jamra, David A. Dyment, Kym M. Boycott, Alexander P. A. Stegmann, Christian Kubisch, Ene-Choo Tan, Ghayda M. Mirzaa, Kirsty McWalter, Tjitske Kleefstra, Rolph Pfundt, Zoya Ignatova, Gunter Meister, and Hans-Jürgen Kreienkamp

Subjects
Science
Abstract

AGO2 binds to miRNAs to repress expression of cognate target mRNAs. Here the authors report that heterozygous AGO2 mutations result in defects in neurological development and impair RNA interference.

Published
2020
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9. Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

Author

Sahar Elouej, Karim Harhouri, Morgane Le Mao, Genevieve Baujat, Sheela Nampoothiri, Hϋlya Kayserili, Nihal Al Menabawy, Laila Selim, Arianne Llamos Paneque, Christian Kubisch, Davor Lessel, Robert Rubinsztajn, Chayki Charar, Catherine Bartoli, Coraline Airault, Jean-François Deleuze, Agnes Rötig, Peter Bauer, Catarina Pereira, Abigail Loh, Nathalie Escande-Beillard, Antoine Muchir, Lisa Martino, Yosef Gruenbaum, Song-Hua Lee, Philippe Manivet, Guy Lenaers, Bruno Reversade, Nicolas Lévy, and Annachiara De Sandre-Giovannoli

Subjects
Science
Abstract

Mandibuloacral dysplasias (MADs) are rare progeroid syndromes characterized by nuclear morphological and functional abnormalities. Here the authors report that loss of mitochondrial membrane protein MTX2 causes a progeroid MAD sharing clinical features with lamin-associated progeroid syndromes.

Published
2020
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10. Publisher Correction: Shared heritability and functional enrichment across six solid cancers

Author

Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R. Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H. M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström

Subjects
Science
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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11. SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication

Author

Swagata Halder, Ignacio Torrecilla, Martin D. Burkhalter, Marta Popović, John Fielden, Bruno Vaz, Judith Oehler, Domenic Pilger, Davor Lessel, Katherine Wiseman, Abhay Narayan Singh, Iolanda Vendrell, Roman Fischer, Melanie Philipp, and Kristijan Ramadan

Subjects
Science
Abstract

Cells deficient in SPRTN protease activity exhibit severe DNA-protein crosslink induced replication stress and genome instability. Here the author reveal a functional link between the SPRTN protease and the CHK1 kinase during physiological DNA replication.

Published
2019
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12. Shared heritability and functional enrichment across six solid cancers

Author

Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström

Subjects
Science
Abstract

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Published
2019
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13. Author Correction: Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Author

Marco Matejcic, Edward J. Saunders, Tokhir Dadaev, Mark N. Brook, Kan Wang, Xin Sheng, Ali Amin Al Olama, Fredrick R. Schumacher, Sue A. Ingles, Koveela Govindasami, Sara Benlloch, Sonja I. Berndt, Demetrius Albanes, Stella Koutros, Kenneth Muir, Victoria L. Stevens, Susan M. Gapstur, Catherine M. Tangen, Jyotsna Batra, Judith Clements, Henrik Gronberg, Nora Pashayan, Johanna Schleutker, Alicja Wolk, Catharine West, Lorelei Mucci, Peter Kraft, Géraldine Cancel-Tassin, Karina D. Sorensen, Lovise Maehle, Eli M. Grindedal, Sara S. Strom, David E. Neal, Freddie C. Hamdy, Jenny L. Donovan, Ruth C. Travis, Robert J. Hamilton, Barry Rosenstein, Yong-Jie Lu, Graham G. Giles, Adam S. Kibel, Ana Vega, Jeanette T. Bensen, Manolis Kogevinas, Kathryn L. Penney, Jong Y. Park, Janet L. Stanford, Cezary Cybulski, Børge G. Nordestgaard, Hermann Brenner, Christiane Maier, Jeri Kim, Manuel R. Teixeira, Susan L. Neuhausen, Kim De Ruyck, Azad Razack, Lisa F. Newcomb, Davor Lessel, Radka Kaneva, Nawaid Usmani, Frank Claessens, Paul A. Townsend, Manuela Gago-Dominguez, Monique J. Roobol, Florence Menegaux, Kay-Tee Khaw, Lisa A. Cannon-Albright, Hardev Pandha, Stephen N. Thibodeau, Daniel J. Schaid, The PRACTICAL Consortium, Fredrik Wiklund, Stephen J. Chanock, Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai, David V. Conti, and Christopher A. Haiman

Subjects
Science
Abstract

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019
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14. Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Author

Marco Matejcic, Edward J. Saunders, Tokhir Dadaev, Mark N. Brook, Kan Wang, Xin Sheng, Ali Amin Al Olama, Fredrick R. Schumacher, Sue A. Ingles, Koveela Govindasami, Sara Benlloch, Sonja I. Berndt, Demetrius Albanes, Stella Koutros, Kenneth Muir, Victoria L. Stevens, Susan M. Gapstur, Catherine M. Tangen, Jyotsna Batra, Judith Clements, Henrik Gronberg, Nora Pashayan, Johanna Schleutker, Alicja Wolk, Catharine West, Lorelei Mucci, Peter Kraft, Géraldine Cancel-Tassin, Karina D. Sorensen, Lovise Maehle, Eli M. Grindedal, Sara S. Strom, David E. Neal, Freddie C. Hamdy, Jenny L. Donovan, Ruth C. Travis, Robert J. Hamilton, Barry Rosenstein, Yong-Jie Lu, Graham G. Giles, Adam S. Kibel, Ana Vega, Jeanette T. Bensen, Manolis Kogevinas, Kathryn L. Penney, Jong Y. Park, Janet L. Stanford, Cezary Cybulski, Børge G. Nordestgaard, Hermann Brenner, Christiane Maier, Jeri Kim, Manuel R. Teixeira, Susan L. Neuhausen, Kim De Ruyck, Azad Razack, Lisa F. Newcomb, Davor Lessel, Radka Kaneva, Nawaid Usmani, Frank Claessens, Paul A. Townsend, Manuela Gago-Dominguez, Monique J. Roobol, Florence Menegaux, Kay-Tee Khaw, Lisa A. Cannon-Albright, Hardev Pandha, Stephen N. Thibodeau, Daniel J. Schaid, The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Fredrik Wiklund, Stephen J. Chanock, Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai, David V. Conti, and Christopher A. Haiman

Subjects
Science
Abstract

Chromosome 8q24 is known to be a major susceptibility region for prostate cancer risk. Here the authors analyze genetic data across the 8q24 region from 71,535 prostate cancer patients identifying 12 risk loci, three previously unreported, highlighting the contribution of germline variation at this locus.

Published
2018
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15. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Author

Tokhir Dadaev, Edward J. Saunders, Paul J. Newcombe, Ezequiel Anokian, Daniel A. Leongamornlert, Mark N. Brook, Clara Cieza-Borrella, Martina Mijuskovic, Sarah Wakerell, Ali Amin Al Olama, Fredrick R. Schumacher, Sonja I. Berndt, Sara Benlloch, Mahbubl Ahmed, Chee Goh, Xin Sheng, Zhuo Zhang, Kenneth Muir, Koveela Govindasami, Artitaya Lophatananon, Victoria L. Stevens, Susan M. Gapstur, Brian D. Carter, Catherine M. Tangen, Phyllis Goodman, Ian M. Thompson, Jyotsna Batra, Suzanne Chambers, Leire Moya, Judith Clements, Lisa Horvath, Wayne Tilley, Gail Risbridger, Henrik Gronberg, Markus Aly, Tobias Nordström, Paul Pharoah, Nora Pashayan, Johanna Schleutker, Teuvo L. J. Tammela, Csilla Sipeky, Anssi Auvinen, Demetrius Albanes, Stephanie Weinstein, Alicja Wolk, Niclas Hakansson, Catharine West, Alison M. Dunning, Neil Burnet, Lorelei Mucci, Edward Giovannucci, Gerald Andriole, Olivier Cussenot, Géraldine Cancel-Tassin, Stella Koutros, Laura E. Beane Freeman, Karina Dalsgaard Sorensen, Torben Falck Orntoft, Michael Borre, Lovise Maehle, Eli Marie Grindedal, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Richard M. Martin, Ruth C. Travis, Tim J. Key, Robert J. Hamilton, Neil E. Fleshner, Antonio Finelli, Sue Ann Ingles, Mariana C. Stern, Barry Rosenstein, Sarah Kerns, Harry Ostrer, Yong-Jie Lu, Hong-Wei Zhang, Ninghan Feng, Xueying Mao, Xin Guo, Guomin Wang, Zan Sun, Graham G. Giles, Melissa C. Southey, Robert J. MacInnis, Liesel M. FitzGerald, Adam S. Kibel, Bettina F. Drake, Ana Vega, Antonio Gómez-Caamaño, Laura Fachal, Robert Szulkin, Martin Eklund, Manolis Kogevinas, Javier Llorca, Gemma Castaño-Vinyals, Kathryn L. Penney, Meir Stampfer, Jong Y. Park, Thomas A. Sellers, Hui-Yi Lin, Janet L. Stanford, Cezary Cybulski, Dominika Wokolorczyk, Jan Lubinski, Elaine A. Ostrander, Milan S. Geybels, Børge G. Nordestgaard, Sune F. Nielsen, Maren Weisher, Rasmus Bisbjerg, Martin Andreas Røder, Peter Iversen, Hermann Brenner, Katarina Cuk, Bernd Holleczek, Christiane Maier, Manuel Luedeke, Thomas Schnoeller, Jeri Kim, Christopher J. Logothetis, Esther M. John, Manuel R. Teixeira, Paula Paulo, Marta Cardoso, Susan L. Neuhausen, Linda Steele, Yuan Chun Ding, Kim De Ruyck, Gert De Meerleer, Piet Ost, Azad Razack, Jasmine Lim, Soo-Hwang Teo, Daniel W. Lin, Lisa F. Newcomb, Davor Lessel, Marija Gamulin, Tomislav Kulis, Radka Kaneva, Nawaid Usmani, Chavdar Slavov, Vanio Mitev, Matthew Parliament, Sandeep Singhal, Frank Claessens, Steven Joniau, Thomas Van den Broeck, Samantha Larkin, Paul A. Townsend, Claire Aukim-Hastie, Manuela Gago-Dominguez, Jose Esteban Castelao, Maria Elena Martinez, Monique J. Roobol, Guido Jenster, Ron H. N. van Schaik, Florence Menegaux, Thérèse Truong, Yves Akoli Koudou, Jianfeng Xu, Kay-Tee Khaw, Lisa Cannon-Albright, Hardev Pandha, Agnieszka Michael, Andrzej Kierzek, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Sara Lindstrom, Constance Turman, Jing Ma, David J. Hunter, Elio Riboli, Afshan Siddiq, Federico Canzian, Laurence N. Kolonel, Loic Le Marchand, Robert N. Hoover, Mitchell J. Machiela, Peter Kraft, The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Matthew Freedman, Fredrik Wiklund, Stephen Chanock, Brian E. Henderson, Douglas F. Easton, Christopher A. Haiman, Rosalind A. Eeles, David V. Conti, and Zsofia Kote-Jarai

Subjects
Science
Abstract

Prostate cancer (PrCa) involves a large heritable genetic component. Here, the authors perform multivariate fine-mapping of known PrCa GWAS loci, identifying variants enriched for biological function, explaining more familial relative risk, and with potential application in clinical risk profiling.

Published
2018
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16. Integrated Molecular Characterization of Testicular Germ Cell Tumors

Author

Hui Shen, Juliann Shih, Daniel P. Hollern, Linghua Wang, Reanne Bowlby, Satish K. Tickoo, Vésteinn Thorsson, Andrew J. Mungall, Yulia Newton, Apurva M. Hegde, Joshua Armenia, Francisco Sánchez-Vega, John Pluta, Louise C. Pyle, Rohit Mehra, Victor E. Reuter, Guilherme Godoy, Jeffrey Jones, Carl S. Shelley, Darren R. Feldman, Daniel O. Vidal, Davor Lessel, Tomislav Kulis, Flavio M. Cárcano, Kristen M. Leraas, Tara M. Lichtenberg, Denise Brooks, Andrew D. Cherniack, Juok Cho, David I. Heiman, Katayoon Kasaian, Minwei Liu, Michael S. Noble, Liu Xi, Hailei Zhang, Wanding Zhou, Jean C. ZenKlusen, Carolyn M. Hutter, Ina Felau, Jiashan Zhang, Nikolaus Schultz, Gad Getz, Matthew Meyerson, Joshua M. Stuart, Rehan Akbani, David A. Wheeler, Peter W. Laird, Katherine L. Nathanson, Victoria K. Cortessis, Katherine A. Hoadley, David Wheeler, Daniel Hughes, Kyle Covington, Joy C. Jayaseelan, Viktoriya Korchina, Lora Lewis, Jianhong Hu, HarshaVardhan Doddapaneni, Donna Muzny, Richard Gibbs, Daniel Hollern, Benjamin G. Vincent, Shengjie Chai, Christof C. Smith, J. Todd Auman, Yan Shi, Shaowu Meng, Tara Skelly, Donghui Tan, Umadevi Veluvolu, Piotr A. Mieczkowski, Corbin D. Jones, Matthew D. Wilkerson, Saianand Balu, Tom Bodenheimer, Alan P. Hoyle, Stuart R. Jefferys, Lisle E. Mose, Janae V. Simons, Matthew G. Soloway, Jeffrey Roach, Joel S. Parker, D. Neil Hayes, Charles M. Perou, Gordon Saksena, Carrie Cibulskis, Steven E. Schumacher, Rameen Beroukhim, Stacey B. Gabriel, Adrian Ally, Miruna Balasundaram, Rebecca Carlsen, Dorothy Cheung, Eric Chuah, Noreen Dhalla, Robert A. Holt, Steven J.M. Jones, Yussanne Ma, Michael Mayo, Richard A. Moore, A. Gordon Robertson, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Tina Wong, Marco A. Marra, Daniel J. Weisenberger, David J. Van Den Berg, Phillip H. Lai, Mario Berrios, Andrea Holbrook, Moiz S. Bootwalla, Dennis T. Maglinte, Debyani Chakravarty, Jianjiong Gao, Zachary Heins, Ritika Kundra, Angelica Ochoa, Chris Sander, Marc Ladanyi, Vesteinn Thorsson, Amie J. Radenbaugh, Nils Gehlenborg, Doug Voet, Pei Lin, Scott Frazer, Jaegil Kim, Michael S. Lawrence, Sam Meier, Timothy Defreitas, Lynda Chin, John N. Weinstein, Wenbin Liu, Gordon B. Mills, Yiling Lu, Leendert Looijenga, Alan H. Bryce, André L. Carvalho, Darren Feldman, Michael Ittmann, Seth Lerner, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Carmen Helsel, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Sandra Cottingham, David Chesla, Charles Saller, Katherine Tarvin, Luiz Fernando Lopes, Cristovam Scapulatempo-Neto, Natália D.A. Aredes, Wolter Oosterhuis, Ad Gillis, Hans Stoop, Wil Eijkenboom, George Sandusky, Sue Ellen Martin, Manju Aron, Siamak Daneshmand, Hooman Djaladat, David Quinn, Tanya Dorff, Jochen K. Lennerz, Leigh B. Thorne, Marija Gamulin, Zeljko Kastelan, Tvrtko Hudolin, Christian Kubisch, Lori Boice, Mei Huang, Amy H. Perou, W. Kimryn Rathmell, Todd Pihl, Yunhu Wan, Qiang Sun, Rashi Naresh, Sudha Chudamani, Jia Liu, Laxmi Lolla, Ye Wu, Martin L. Ferguson, Jean C. Zenklusen, Jiashan (Julia) Zhang, Margi Sheth, John A. Demchok, Liming Yang, Zhining Wang, Roy Tarnuzzer, Heidi J. Sofia, and Tanja M. Davidsen

Subjects
Biology (General), QH301-705.5
Abstract

Summary: We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance—KIT, KRAS, and NRAS—exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas. : Shen et al. identify molecular characteristics that classify testicular germ cell tumor types, including a separate subset of seminomas defined by KIT mutations. This provides a set of candidate biomarkers for risk stratification and potential therapeutic targeting. Keywords: The Cancer Genome Atlas, testicular germ cell tumors, seminoma, nonseminoma, DNA methylation, exome sequencing, KIT, copy number, miR-375

Published
2018
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17. Fatal Myelotoxicity Following Palliative Chemotherapy With Cisplatin and Gemcitabine in a Patient With Stage IV Cholangiocarcinoma Linked to Post Mortem Diagnosis of Fanconi Anemia

Author

Nils W. Engel, Simon Schliffke, Ulrich Schüller, Christian Frenzel, Carsten Bokemeyer, Christian Kubisch, and Davor Lessel

Subjects
fanconi anemia, FANCA, cholangiocarcinoma, genomic instability, myelotoxicity, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Unrecognized genome instability syndromes can potentially impede the rational treatment of cancer in rare patients. Identification of cancer patients with a hereditary condition is a compelling necessity for oncologists, giving varying hypersensitivities to various chemotherapeutic agents or radiation, depending on the underlying genetic cause. Omission of genetic testing in the setting of an overlooked hereditary syndrome may lead to unexpected and unbearable toxicity from oncological standard approaches. We present a case of a 33-year-old man with an early-onset stage IV intrahepatic cholangiocarcinoma, who experienced unusual bone marrow failure and neutropenic fever syndrome as a consequence of palliative chemotherapy containing cisplatin and gemcitabine, leading to a fatal outcome on day 25 of his first chemotherapeutic cycle. The constellation of bone marrow failure after exposure to the platinum-based agent cisplatin, the presence of an early-onset solid malignancy and the critical appraisal of further phenotypical features raised suspicion of a hereditary genome instability syndrome. Whole-exome sequencing from buccal swab DNA enabled the post mortem diagnosis of Fanconi anemia, most likely linked to the fatal outcome due to utilization of the DNA crosslinking agent cisplatin. The patient's phenotype was exceptional, as he never displayed significant hematologic abnormalities, which is the hallmark of Fanconi anemia. As such, this case stresses the importance to at least question the possibility of a hereditary basis in cases of relatively early-onset malignancy before defining an oncological treatment strategy.

Published
2019
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18. Author Correction: Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

Author

Sahar Elouej, Karim Harhouri, Morgane Le Mao, Genevieve Baujat, Sheela Nampoothiri, Hϋlya Kayserili, Nihal Al Menabawy, Laila Selim, Arianne Llamos Paneque, Christian Kubisch, Davor Lessel, Robert Rubinsztajn, Chayki Charar, Catherine Bartoli, Coraline Airault, Jean-François Deleuze, Agnes Rötig, Peter Bauer, Catarina Pereira, Abigail Loh, Nathalie Escande-Beillard, Antoine Muchir, Lisa Martino, Yosef Gruenbaum, Song-Hua Lee, Philippe Manivet, Guy Lenaers, Bruno Reversade, Nicolas Lévy, and Annachiara De Sandre-Giovannoli

Subjects
Science
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020
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19. Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy

Author

Shehrazade Dahimene, Leonie von Elsner, Tess Holling, Lauren S Mattas, Jess Pickard, Davor Lessel, Kjara S Pilch, Ivan Kadurin, Wendy S Pratt, Igor B Zhulin, Hongzheng Dai, Maja Hempel, Maura R Z Ruzhnikov, Kerstin Kutsche, and Annette C Dolphin

Subjects
Mammals, Neurons, Calcium Channels, N-Type, Epilepsy, Calcium Channels, L-Type, Cell Membrane, Animals, Humans, Calcium, Calcium Channels, Neurology (clinical), Age of Onset
Abstract

Voltage-gated calcium (CaV) channels form three subfamilies (CaV1–3). The CaV1 and CaV2 channels are heteromeric, consisting of an α1 pore-forming subunit, associated with auxiliary CaVβ and α2δ subunits. The α2δ subunits are encoded in mammals by four genes, CACNA2D1–4. They play important roles in trafficking and function of the CaV channel complexes. Here we report biallelic variants in CACNA2D1, encoding the α2δ-1 protein, in two unrelated individuals showing a developmental and epileptic encephalopathy. Patient 1 has a homozygous frameshift variant c.818_821dup/p.(Ser275Asnfs*13) resulting in nonsense-mediated mRNA decay of the CACNA2D1 transcripts, and absence of α2δ-1 protein detected in patient-derived fibroblasts. Patient 2 is compound heterozygous for an early frameshift variant c.13_23dup/p.(Leu9Alafs*5), highly probably representing a null allele and a missense variant c.626G>A/p.(Gly209Asp). Our functional studies show that this amino-acid change severely impairs the function of α2δ-1 as a calcium channel subunit, with strongly reduced trafficking of α2δ-1G209D to the cell surface and a complete inability of α2δ-1G209D to increase the trafficking and function of CaV2 channels. Thus, biallelic loss-of-function variants in CACNA2D1 underlie the severe neurodevelopmental disorder in these two patients. Our results demonstrate the critical importance and non-interchangeability of α2δ-1 and other α2δ proteins for normal human neuronal development.

Published
2022

20. Werner syndrome in a Lebanese family

Author

Batoul Jaafar, Mona Nasrallah, Bianca Sievers, Junko Oshima, and Davor Lessel

Subjects
Genetics, Article, Genetics (clinical)
Abstract

Werner syndrome (WS) is an extremely rare, autosomal recessive segmental progeroid disorder caused by biallelic pathogenic variants in the WRN, which encodes a multifunctional nuclear protein that belongs to the RecQ family of DNA helicases. Despite extensive research on WS in the last years, the population-specific mutational spectrum still needs to be elucidated. Moreover, there is an evident lack of detailed clinical descriptions accompanied with photographs of affected individuals. Here, we report a consanguineous Lebanese family in whom we identified a pathogenic homozygous nonsense variant c.1111G>T, p.Glu371* in the WRN. The index individual, at the age of 54 years, was suspected to have WS due to a history of early-onset cataracts, premature hair loss and graying, chronic non-healing leg ulcers, Achilles’ tendon calcifications, type 2 diabetes mellitus, dyslipidemia, hypothyroidism and premature coronary artery disease. His four sisters, three of which deceased in the fifth decade, had clinical signs suggestive of WS. Moreover, his daughter, aged 23 years, had short stature, hair loss and flat feet. Taken together, we report a detailed clinical course of disease in several affected members of a consanguineous family, which is additionally documented by photographs.

Published
2022

21. Variant-specific effects define the phenotypic spectrum of HNRNPH2-associated neurodevelopmental disorders in males

Author

Hans-Jürgen Kreienkamp, Matias Wagner, Heike Weigand, Allyn McConkie-Rossell, Marie McDonald, Boris Keren, Cyril Mignot, Julie Gauthier, Jean-François Soucy, Jacques L. Michaud, Meghan Dumas, Rosemarie Smith, Ulrike Löbel, Maja Hempel, Christian Kubisch, Jonas Denecke, Philippe M. Campeau, Jennifer M. Bain, and Davor Lessel

Subjects
Male, Adolescent, Mutation, Missense, Original Investigation, Human Genetics, Molecular Medicine, Gene Function, Metabolic Diseases, Young Adult, Intellectual Disability, Diseases in Twins, Genetics, Humans, RNA-Seq, Child, Frameshift Mutation, Genetic Association Studies, Genetics (clinical), Chromosomes, Human, X, Heterogeneous-Nuclear Ribonucleoprotein Group F-H, Brain, Genetic Variation, Twins, Monozygotic, ddc, Alternative Splicing, Phenotype, Amino Acid Substitution, Codon, Nonsense, Neurodevelopmental Disorders, Child, Preschool, Mutation, Female
Abstract

Bain type of X-linked syndromic intellectual developmental disorder, caused by pathogenic missense variants in HRNRPH2, was initially described in six female individuals affected by moderate-to-severe neurodevelopmental delay. Although it was initially postulated that the condition would not be compatible with life in males, several affected male individuals harboring pathogenic variants in HNRNPH2 have since been documented. However, functional in-vitro analyses of identified variants have not been performed and, therefore, possible genotype–phenotype correlations remain elusive. Here, we present eight male individuals, including a pair of monozygotic twins, harboring pathogenic or likely pathogenic HNRNPH2 variants. Notably, we present the first individuals harboring nonsense or frameshift variants who, similarly to an individual harboring a de novo p.(Arg29Cys) variant within the first quasi-RNA-recognition motif (qRRM), displayed mild developmental delay, and developed mostly autistic features and/or psychiatric co-morbidities. Additionally, we present two individuals harboring a recurrent de novo p.(Arg114Trp), within the second qRRM, who had a severe neurodevelopmental delay with seizures. Functional characterization of the three most common HNRNPH2 missense variants revealed dysfunctional nucleocytoplasmic shuttling of proteins harboring the p.(Arg206Gln) and p.(Pro209Leu) variants, located within the nuclear localization signal, whereas proteins with p.(Arg114Trp) showed reduced interaction with members of the large assembly of splicing regulators (LASR). Moreover, RNA-sequencing of primary fibroblasts of the individual harboring the p.(Arg114Trp) revealed substantial alterations in the regulation of alternative splicing along with global transcriptome changes. Thus, we further expand the clinical and variant spectrum in HNRNPH2-associated disease in males and provide novel molecular insights suggesting the disorder to be a spliceopathy on the molecular level.

Published
2021

22. A novel homozygous synonymous variant further expands the phenotypic spectrum of <scp>POLR3A</scp> ‐ related pathologies

Author

Christian Kubisch, Katrin Rading, Davor Lessel, Janine Altmüller, Leslie B. Gordon, Susan E. Campbell, and Holger Thiele

Subjects
Adult, Pathology, medicine.medical_specialty, Adolescent, Anodontia, Neonatal Progeroid Syndrome, Progeria, Hypogonadotropic hypogonadism, Genetics, medicine, Humans, Spinocerebellar Ataxias, Genetics (clinical), Muscular hypotonia, business.industry, Leukodystrophy, Infant, Newborn, RNA Polymerase III, medicine.disease, Optic Atrophy, Aphonia, Ataxia, Female, medicine.symptom, Lipodystrophy, business, Spastic quadriplegia
Abstract

Pathogenic biallelic variants in POL3RA have been associated with different disorders characterized by progressive neurological deterioration. These include the 4H leukodystrophy syndrome (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) and adolescent-onset progressive spastic ataxia, as well as Wiedemann-Rautenstrauch syndrome (WRS), a recognizable neonatal progeroid syndrome. The phenotypic differences between these disorders are thought to occur mainly due to different functional effects of underlying POLR3A variants. Here we present the detailed clinical course of a 37-year-old woman in whom we identified a homozygous synonymous POLR3A variant c.3336G>A resulting in leaky splicing r.[3336ins192, =, 3243_3336del94]. She presented at birth with intrauterine growth retardation, lipodystrophy, muscular hypotonia, and several WRS-like facial features, albeit without sparse hair and prominent scalp veins. She had no signs of developmental delay or intellectual disability. Over the years, above characteristic facial features, she showed severe postnatal growth retardation, global lipodystrophy, joint contractures, thoracic hypoplasia, scoliosis, anodontia, spastic quadriplegia, bilateral hearing loss, aphonia, hypogonadotropic hypogonadism, and cerebellar peduncles hyperintensities in brain imaging. These manifestations partially overlap the clinical features of the previously reported POLR3A-associated disorders, mostly mimicking the WRS. Thus, our study expands the POLR3A-mediated phenotypic spectrum and suggests existence of a phenotypic continuum underlying biallelic POLR3A variants.

Published
2021

23. Comprehensive Clinical and Genetic Analysis of CHEK2 in Croatian Men with Prostate Cancer

Author

Kira Kirchner, Marija Gamulin, Tomislav Kulis, Bianca Sievers, Zeljko Kastelan, and Davor Lessel

Subjects
Male, Prostatic Neoplasms / pathology, Checkpoint Kinase 2 / genetics, Croatia, CHEK2, aggressive prostate cancer, prostate cancer, Genetics, Prostatic Neoplasms / genetics, Humans, Neoplasm Grading, Prostate / pathology, Genetics (clinical), Germ-Line Mutation
Abstract

Germline pathogenic and likely pathogenic (P/LP) variants in CHEK2 have been associated with increased prostate cancer (PrCa) risk. Our objective was to analyze their occurrence in Croatian PrCa men and to evaluate the clinical characteristics of P/LP variant carriers. Therefore, we analyzed CHEK2 in 150 PrCa patients unselected for age of onset, family history of PrCa or clinical outcome, and the frequency of identified variants was compared to findings in 442 cancer-free men, of Croatian ancestry. We identified four PrCa cases harboring a P/LP variant in CHEK2 (4/150, 2.67%), which reached a statistical significance (p = 0.004) as compared to the control group. Patients with P/LP variants in CHEK2 developed PrCa almost 9 years earlier than individuals with CHEK2 wild-type alleles (8.9 years; p = 0.0198) and had an increased risk for lymph node involvement (p = 0.0047). No association was found between CHEK2 status and further clinical characteristics, including the Gleason score, occurrence of aggressive PrCa, the tumor or metastasis stage. However, carriers of the most common P/LP CHEK2 variant, the c.1100delC, p.Thr367Metfs15*, had a significantly higher Gleason score (p = 0.034), risk for lymph node involvement (p = 0.0001), and risk for developing aggressive PrCa (p = 0.027). Thus, in a Croatian population, CHEK2 P/LP variant carriers were associated with increased risk for early onset prostate cancer, and carriers of the c.1100delC, p.Thr367Metfs15* had increased risk for aggressive PrCa.

Published
2022

24. Comprehensive Clinical and Genetic Analysis of

Author

Kira, Kirchner, Marija, Gamulin, Tomislav, Kulis, Bianca, Sievers, Zeljko, Kastelan, and Davor, Lessel

Subjects
Male, Checkpoint Kinase 2, Croatia, Prostate, Humans, Prostatic Neoplasms, Neoplasm Grading, Germ-Line Mutation
Abstract

Germline pathogenic and likely pathogenic (P/LP) variants in

Published
2022

25. Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration

Author

Sima Khazaei, Carol C.L. Chen, Augusto Faria Andrade, Nisha Kabir, Pariya Azarafshar, Shahir M. Morcos, Josiane Alves França, Mariana Lopes, Peder J. Lund, Geoffroy Danieau, Samantha Worme, Lata Adnani, Nadine Nzirorera, Xiao Chen, Gayathri Yogarajah, Caterina Russo, Michele Zeinieh, Cassandra J. Wong, Laura Bryant, Steven Hébert, Bethany Tong, Tianna S. Sihota, Damien Faury, Evan Puligandla, Wajih Jawhar, Veronica Sandy, Mitra Cowan, Emily M. Nakada, Loydie A. Jerome-Majewska, Benjamin Ellezam, Carolina Cavalieri Gomes, Jonas Denecke, Davor Lessel, Marie T. McDonald, Carolyn E. Pizoli, Kathryn Taylor, Benjamin T. Cocanougher, Elizabeth J. Bhoj, Anne-Claude Gingras, Benjamin A. Garcia, Chao Lu, Eric I. Campos, Claudia L. Kleinman, Livia Garzia, and Nada Jabado

Subjects
General Biochemistry, Genetics and Molecular Biology
Published
2023

26. Whole-Exome Sequencing in Critically Ill Neonates and Infants: Diagnostic Yield and Predictability of Monogenic Diagnosis

Author

Amelie T van der Ven, Nadia Obi, Tatjana Bierhals, Philipp Deindl, Martin Blohm, Dominique Singer, Jessika Johannsen, Davor Lessel, Katja Kloth, Maja Hempel, Anna Perez, Theresia Herget, Christian Kubisch, Jasmin Lisfeld, Tasja Scholz, René Santer, Fanny Kortüm, and Jonas Denecke

Subjects
Pediatrics, medicine.medical_specialty, Critically ill, business.industry, Critical Illness, Infant, First year of life, Disease, Intensive care unit, law.invention, Intensive Care Units, Phenotype, Genetic etiology, law, Exome Sequencing, Pediatrics, Perinatology and Child Health, Human Phenotype Ontology, Cohort, Humans, Medicine, Genetic Testing, business, Exome sequencing, Developmental Biology
Abstract

Introduction: Monogenic diseases play an important role in critically ill neonates and infants treated in the intensive care unit. This study aimed to determine the diagnostic yield of whole-exome sequencing (WES) for monogenic diseases and identify phenotypes more likely associated with a genetic etiology. Methods: From March 2017 to 2020, a comprehensive diagnostic workup including WES in a single academic center was performed in 61 unrelated, critically ill neonates and infants with an unknown underlying disease within the first year of life. We conducted 59 trio-WES, 1 duo-WES, and 1 single-WES analyses. Symptoms were classified according to the Human Phenotype Ontology. Results: The overall molecular genetic diagnostic rate within our cohort was 46% (28/61) and 50% (15/30) in the subgroup of preterm neonates. Identifying the genetic cause of disease facilitates individualized management in the majority of patients. A positive or negative predictive power of specific clinical features for a genetic diagnosis could not be observed. Conclusion: WES is a powerful noninvasive diagnostic tool in critically ill neonates and infants with a high diagnostic rate. We recommend initiating WES as early as possible due to the impact on management and family counseling. Recommendations regarding the clinical utility of WES in critically ill neonates and infants should not be based on the phenotype alone. Here, we present a clinical workflow for the application of WES for critically ill neonates and infants in an interdisciplinary setting.

Published
2021

27. Biallelic PAN2 variants in individuals with a syndromic neurodevelopmental disorder and multiple congenital anomalies

Author

Miriam S. Reuter, Michael Zech, Maja Hempel, Janine Altmüller, Tracy Heung, Laura Pölsler, René Santer, Holger Thiele, Brett Trost, Christian Kubisch, Stephen W. Scherer, Sabine Rudnik-Schöneborn, Anne S. Bassett, Davor Lessel, and Medical Genetics

Subjects
Phenotype, Neurodevelopmental Disorders, Intellectual Disability, Genetics, Humans, Muscle Hypotonia, Abnormalities, Multiple, Dwarfism, RNA, Messenger, Genetics (clinical), Article
Abstract

PAN2 encodes a subunit of a deadenylation complex with important functions in mRNA stability and post-transcriptional regulation of gene expression. A homozygous frameshift deletion in PAN2 was reported in a single affected individual with developmental delay and multiple congenital anomalies. Here, we describe five additional individuals from three unrelated families with homozygous predicted loss-of-function variants in PAN2. The affected individuals presented with significant overlap in their clinical features, including mild-moderate intellectual disability, hypotonia, sensorineural hearing loss, EEG abnormalities, congenital heart defects (tetralogy of Fallot, septal defects, dilated aortic root), urinary tract malformations, ophthalmological anomalies, short stature with other skeletal anomalies, and craniofacial features including flat occiput, ptosis, long philtrum, and short neck. Our data confirm that biallelic predicted loss-of-function variants in PAN2 cause a syndrome with multiple congenital anomalies, and suggest an important role of mRNA polyA tail length for proper organ formation.

Published
2022

28. Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

Author

Robert A. Hegele, Maria Iascone, Kevin A. Shapiro, Nicolas Chatron, Marwan Shinawi, Joel Charrow, Jeffrey W. Innis, Luitgard Graul-Neumann, Joanna Goes Castro Meira, Anna Lehman, Dawn L. Earl, Victoria R. Sanders, Shannon Rego, David A. Sweetser, Clémantine Dimartino, Wilhelmina S. Kerstjens-Frederikse, Antonio Vitobello, Davor Lessel, Daniel Grinberg, Laurence Faivre, Ryan Peretz, Katherine M. Christensen, Emma Reesor, Erin Beaver, Elizabeth Wohler, Margot R.F. Reijnders, Deborah Barbouth, Anna Cereda, Kaja Kristine Selmer, Melissa A. Walker, Barbro Stadheim, Alessandro Serretti, Helen Kingston, Jill Clayton-Smith, Raymond Lewandowski, Bernarda Lozić, Robert Stratton, Amelia Kirby, Anne H. O’Donnell-Luria, Sara Gabbiadini, Susanna Balcells, Myriam Oufadem, Christel Thauvin, Maha Aly, Wendy K. Chung, Susan M. White, Lauren C. Briere, Thomas Smol, Stanislas Lyonnet, Roberto Colombo, Catherine E. Keegan, Marie T. McDonald, Melanie Parisot, Tiong Yang Tan, Brian Wong, Christopher T. Gordon, Magnus Dehli Vigeland, Frances A. High, Emily Bryant, Audrey Labalme, Nara Sobreira, Arnold Munnich, Jeanne Amiel, Dayna Morel Swols, Raquel Rabionet, Laura Castilla-Vallmanya, Jennifer Heeley, Gunnar Houge, Michael J. Gambello, Bernardo Blanco-Sánchez, Lynn Pais, Olena M. Vaske, Roser Urreizti, Alison Wray, Veronique Pingault, Damien Sanlaville, John Christodoulou, John Millichap, Valérie Cormier-Daire, Parul Jayakar, Helen Cox, Frédéric Tran Mau-Them, Belinda Chong, Victoria Mok Siu, Anne Slavotinek, Antonie J. van Essen, Ingvild Aukrust, Lorne A. Clarke, Rachel Gannaway, Anne Dieux-Coeslier, Patrick Nitschké, Tony Yao, Simon Sadedin, Danielle Karlowicz, Christelle Rougeot, Christine Bole-Feysot, Sandra Yang, Megan T. Cho, Gaetan Lesca, Christiane Zweier, Castilla-Vallmanya L., Selmer K.K., Dimartino C., Rabionet R., Blanco-Sanchez B., Yang S., Reijnders M.R.F., van Essen A.J., Oufadem M., Vigeland M.D., Stadheim B., Houge G., Cox H., Kingston H., Clayton-Smith J., Innis J.W., Iascone M., Cereda A., Gabbiadini S., Chung W.K., Sanders V., Charrow J., Bryant E., Millichap J., Vitobello A., Thauvin C., Mau-Them F.T., Faivre L., Lesca G., Labalme A., Rougeot C., Chatron N., Sanlaville D., Christensen K.M., Kirby A., Lewandowski R., Gannaway R., Aly M., Lehman A., Clarke L., Graul-Neumann L., Zweier C., Lessel D., Lozic B., Aukrust I., Peretz R., Stratton R., Smol T., Dieux-Coeslier A., Meira J., Wohler E., Sobreira N., Beaver E.M., Heeley J., Briere L.C., High F.A., Sweetser D.A., Walker M.A., Keegan C.E., Jayakar P., Shinawi M., Kerstjens-Frederikse W.S., Earl D.L., Siu V.M., Reesor E., Yao T., Hegele R.A., Vaske O.M., Rego S., Shapiro K.A., Wong B., Gambello M.J., McDonald M., Karlowicz D., Colombo R., Serretti A., Pais L., O'Donnell-Luria A., Wray A., Sadedin S., Chong B., Tan T.Y., Christodoulou J., White S.M., Slavotinek A., Barbouth D., Morel Swols D., Parisot M., Bole-Feysot C., Nitschke P., Pingault V., Munnich A., Cho M.T., Cormier-Daire V., Balcells S., Lyonnet S., Grinberg D., Amiel J., Urreizti R., Gordon C.T., MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output

Subjects
0301 basic medicine, NF-KAPPA-B, PROTEIN, 030105 genetics & heredity, medicine.disease_cause, Germline, Transcriptome, ACTIVATION, POLYUBIQUITINATION, Missense mutation, Exome, Genetics (clinical), Genetics, Sanger sequencing, Mutation, leads, Necrosi, craniofacial development, Phenotype, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, intellectual disability, patent ductus arteriosu, symbols, Mutation, Missense, Biology, traf7, Article, akt1, target, 03 medical and health sciences, symbols.namesake, Necrosis, patent ductus arteriosus, medicine, Humans, blepharophimosi, Tumors, MUTATIONS, Fibroblasts, medicine.disease, Blepharophimosis, TRAF7, blepharophimosis, GENOMIC ANALYSIS, Germ Cells, 030104 developmental biology, MENINGIOMAS
Abstract

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

Published
2020

29. Nine newly identified individuals refine the phenotype associated with MYT1L mutations

Author

Jessika Johannsen, Jonas Denecke, Roberto Colombo, Tatjana Bierhals, Marta Bertoli, Franziska Degenhardt, Eva Wohlleber, Tim M. Strom, Alexander M. Zink, Jessica Becker, Davor Lessel, Elisabeth Mangold, Dagmar Wieczorek, Laura M Yates, Kirsten Cremer, Hartmut Engels, Kerstin U. Ludwig, Sophia Peters, Theresia Herget, Maja Hempel, Isabelle C Windheuser, and Hela Hundertmark

Subjects
Adult, Male, 0301 basic medicine, Microcephaly, Adolescent, Medizin, Nerve Tissue Proteins, Haploinsufficiency, 030105 genetics & heredity, Biology, Polymorphism, Single Nucleotide, Short stature, Young Adult, 03 medical and health sciences, Intellectual Disability, Exome Sequencing, Intellectual disability, Genetics, medicine, Humans, Point Mutation, Genetic Predisposition to Disease, Obesity, Child, Genetics (clinical), Exome sequencing, Point mutation, Macrocephaly, Microarray Analysis, medicine.disease, Phenotype, 030104 developmental biology, Child, Preschool, Chromosomes, Human, Pair 2, Female, Chromosomal Microarray, Microdeletion 2p25, 3, Myt1l, Whole Exome Sequencing, Chromosome Deletion, medicine.symptom, Transcription Factors
Abstract

Both point mutations and deletions of the MYT1L gene as well as microdeletions of chromosome band 2p25.3 including MYT1L are associated with intellectual disability, obesity, and behavioral problems. Thus, MYT1L is assumed to be the-at least mainly-causative gene in the 2p25.3 deletion syndrome. Here, we present comprehensive descriptions of nine novel individuals bearing MYT1L mutations; most of them single nucleotide variants (SNVs). This increases the number of known individuals with causative deletions or SNVs of MYT1L to 51. Since eight of the nine novel patients bear mutations affecting MYT1L only, the total number of such individuals now nearly equals the number of individuals with larger microdeletions affecting additional genes, allowing for a comprehensive phenotypic comparison of these two patient groups. For example, 55% of the individuals with mutations affecting MYT1L only were overweight or obese as compared to 86% of the individuals with larger microdeletions. A similar trend was observed regarding short stature with 5 versus 35%, respectively. However, these differences were nominally significant only after correction for multiple testing, further supporting the hypothesis that MYT1L haploinsufficiency is central to the 2p25.3 deletion phenotype. Most importantly, the large number of individuals with MYT1L mutations presented and reviewed here allowed for the delineation of a more comprehensive clinical picture. Seizures, postnatal short stature, macrocephaly, and microcephaly could be shown to be over-represented among individuals with MYT1L mutations.

Published
2020

30. The CHEK2 variant C.349A>G is associated with prostate cancer risk and carriers share a common ancestor

Author

Manuela Gago-Dominguez, Karina Dalsgaard Sørensen, Radka Kaneva, Canary Pass Investigators, Rosalind A. Eeles, Stella Koutros, Kim De Ruyck, Sonja I. Berndt, Manolis Kogevinas, Sofia Maia, Eli Marie Grindedal, Christopher J. Logothetis, Davor Lessel, Nora Pashayan, Ana Peixoto, Catarina Santos, Nawaid Usmani, Zsofia Kote-Jarai, Olivier Cussenot, Esther M. John, Christopher A. Haiman, Catherine M. Tangen, Jong Y. Park, Lorelei A. Mucci, Johanna Schleutker, Ruth C. Travis, Andreia Brandão, Sune F. Nielsen, Manuel R. Teixeira, Melissa C. Southey, Ana Vega, Adam S. Kibel, Ying Wang, Børge G. Nordestgaard, Cezary Cybulski, Jyotsna Batra, Kenneth Muir, Henrik Grönberg, Janet L. Stanford, Lisa F. Newcomb, Hermann Brenner, Manuela Pinheiro, Apcb BioResource, David E. Neal, Marta Cardoso, Paula Paulo, Barry S. Rosenstein, Monique J. Roobol, Robert J. Hamilton, Catharine M L West, Frank Claessens, Paul A. Townsend, Kathryn L. Penney, Susan L. Neuhausen, Alicja Wolk, Christiane Maier, Demetrius Albanes, Fredrik Wiklund, Maria P. Silva, Azad Hassan Abdul Razack, Sue A. Ingles, Urology, Brandão, Andreia [0000-0003-0938-1543], Eeles, Rosalind A [0000-0002-3698-6241], Muir, Kenneth [0000-0001-6429-988X], Schleutker, Johanna [0000-0002-1863-0305], Wang, Ying [0000-0002-1241-6252], Pashayan, Nora [0000-0003-0843-2468], Nordestgaard, Børge G [0000-0002-1954-7220], Sørensen, Karina Dalsgaard [0000-0002-4902-5490], Cybulski, Cezary [0000-0002-2819-3057], Park, Jong Y [0000-0002-6384-6447], Wiklund, Fredrik [0000-0002-4623-0544], Brenner, Hermann [0000-0002-6129-1572], Lessel, Davor [0000-0003-4496-244X], Gago-Dominguez, Manuela [0000-0001-6713-4351], Roobol, Monique J [0000-0001-6967-1708], Teixeira, Manuel R [0000-0002-4896-5982], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Cancer Research, SUSCEPTIBILITY LOCI, Cancer-Predisposing Gene, ancer predisposition, cancer predisposition, Biology, WHOLE-GENOME ASSOCIATION, CHEK2-ASTERISK-1100DELC, lcsh:RC254-282, G84E GERMLINE MUTATION, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, SDG 3 - Good Health and Well-being, medicine, BREAST-CANCER, Missense mutation, CHEK2, METAANALYSIS, Prostate cancer risk, Genetics, Cancer och onkologi, Science & Technology, founder variant, Manchester Cancer Research Centre, MISMATCH REPAIR GENES, ResearchInstitutes_Networks_Beacons/mcrc, Haplotype, 1100DELC, HOXB13, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, prostate cancer, BRCA2, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Relative risk, Cancer and Oncology, Life Sciences & Biomedicine, SNP array
Abstract

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families. We thank the funding support from IPO-Porto Research Center (CI-IPOP-16-2012) and from Fundação para a Ciência e a Tecnologia (FCT; PEst-OE/SAU/ UI0776/2014 and PTDC/DTP-PIC/1308/2014). The following authors were awarded with grants from FCT: PPa (UID/DTP/00776/2013/POCI-01-0145-FEDER-006868), SM (SFRH/BD/71397/2010) and PPi (SFRH/BD/73719/2010). The PRACTICAL consortium (http://practical.icr.ac.uk/) was supported by the Canadian Institutes of Health Research, European Commission’s Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant: No. 1 U19 CA 148537-01 (the GAME-ON initiative). Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) [U19 CA 148537 for ELucidating Loci Involved in Prostate cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I] and by Cancer Research UK grant A8197/A16565. Additional analytic support was provided by NIH NCI U01 CA188392 (PI: Schumacher). We would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now PCUK), The Orchid Cancer Appeal, Rosetrees Trust, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, NIHR funding to the Manchester Biomedical Research Centre and the Manchester Academic Health Sciences Centre.

Published
2020

31. Association study between polymorphisms in DNA methylation-related genes and testicular germ cell tumor risk

Author

Chiara Grasso, Maja Popovic, Elena Isaevska, Fulvio Lazzarato, Valentina Fiano, Daniela Zugna, John Pluta, Benita Weathers, Kurt D'Andrea, Kristian Almstrup, Lynn Anson-Cartwright, D. Timothy Bishop, Stephen J. Chanock, Chu Chen, Victoria K. Cortessis, Marlene D. Dalgaard, Siamak Daneshmand, Alberto Ferlin, Carlo Foresta, Megan N. Frone, Marija Gamulin, Jourik A. Gietema, Mark H. Greene, Tom Grotmol, Robert J. Hamilton, Trine B. Haugen, Russ Hauser, Robert Karlsson, Lambertus A. Kiemeney, Davor Lessel, Patrizia Lista, Ragnhild A. Lothe, Chey Loveday, Coby Meijer, Kevin T. Nead, Jérémie Nsengimana, Rolf I. Skotheim, Clare Turnbull, David J. Vaughn, Fredrik Wiklund, Tongzhang Zheng, Andrea Zitella, Stephen M. Schwartz, Katherine A. McGlynn, Peter A. Kanetsky, Katherine L. Nathanson, Lorenzo Richiardi, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Male, Epidemiology, testicular germ cell tumors (TGCT), DNA methylation-related genes, Single Nucleotide, Neoplasms, Germ Cell and Embryonal, DNA Methylation, Polymorphism, Single Nucleotide, Article, Seminoma, Folic Acid, Testicular Neoplasms, Oncology, Neoplasms, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Genome-Wide Association Study, Humans, Germ Cell and Embryonal, Polymorphism
Abstract

Background: Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation. Methods: In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation–related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls. Results: In individual SNP analyses, seven SNPs, four mapping within MTHFR, were associated with TGCT risk after correction for multiple testing (q ≤ 0.05). Queries of public databases showed that three of these SNPs were associated with MTHFR changes in enzymatic activity (rs1801133) or expression level in testis tissue (rs12121543, rs1476413). Gene-based analyses revealed MTHFR (q = 8.4 × 10–4), methyl-CpG–binding protein 2 (MECP2; q = 2 × 10–3), and ZBTB4 (q = 0.03) as the top TGCT-associated genes. Stratifying by tumor histology, four MTHFR SNPs were associated with seminoma. In gene-based analysis MTHFR was associated with risk of seminoma (q = 2.8 × 10–4), but not with nonseminomatous tumors (q = 0.22). Conclusions: Genetic variants within MTHFR, potentially having an impact on the DNA methylation pattern, are associated with TGCT risk. Impact: This finding suggests that TGCT pathogenesis could be associated with the folate cycle status, and this relation could be partly due to hereditary factors.

Published
2022

32. Intake patterns of specific alcoholic beverages by prostate cancer status

Author

Hui-Yi, Lin, Tung-Sung, Tseng, Xinnan, Wang, Zhide, Fang, Arnold H, Zea, Liang, Wang, Julio, Pow-Sang, Catherine M, Tangen, Phyllis J, Goodman, Alicja, Wolk, Niclas, Håkansson, Manolis, Kogevinas, Javier, Llorca, Hermann, Brenner, Ben, Schöttker, Jose Esteban, Castelao, Manuela, Gago-Dominguez, Marija, Gamulin, Davor, Lessel, Frank, Claessens, Steven, Joniau, The Practical Consortium, Jong Y, Park, and Universidad de Cantabria

Subjects
aggressiveness, alcohol, beverage, prostate cance, Cancer Research, Cancer och onkologi, Prostate cancer, food and beverages, urologic and male genital diseases, prostate cancer, Aggressiveness, Oncology, Cancer and Oncology, Alcohol, Beverage
Abstract

Simple Summary Previous studies have shown heavy intake of different alcoholic beverages affects prostate cancer (PCa) clinical outcomes differently. However, the intake patterns of specific alcoholic beverages for PCa status are understudied. The study's objective is to evaluate intake patterns of total alcohol and three types of alcoholic beverage (beer, wine, and spirits) by PCa risk and aggressiveness status. This study included 10,029 men with European ancestry (4676 non-PCa men and 5353 PCa patients). We found PCa patients had a similar total heavy alcohol intake compared with non-PCa men. However, PCa patients were likely to drink more wine and spirits than non-PCa men. Patients with aggressive PCa drank more beer but not wine and spirits. Interestingly, heavy wine intake was inversely associated with PCa aggressiveness. These findings suggest that the intake patterns of specific alcoholic beverages differ by PCa status, and this information might help develop personalized alcohol intervention for PCa patients. Background: Previous studies have shown that different alcoholic beverage types impact prostate cancer (PCa) clinical outcomes differently. However, intake patterns of specific alcoholic beverages for PCa status are understudied. The study's objective is to evaluate intake patterns of total alcohol and the three types of beverage (beer, wine, and spirits) by the PCa risk and aggressiveness status. Method: This is a cross-sectional study using 10,029 men (4676 non-PCa men and 5353 PCa patients) with European ancestry from the PCa consortium. Associations between PCa status and alcohol intake patterns (infrequent, light/moderate, and heavy) were tested using multinomial logistic regressions. Results: Intake frequency patterns of total alcohol were similar for non-PCa men and PCa patients after adjusting for demographic and other factors. However, PCa patients were more likely to drink wine (light/moderate, OR = 1.11, p = 0.018) and spirits (light/moderate, OR = 1.14, p = 0.003; and heavy, OR = 1.34, p = 0.04) than non-PCa men. Patients with aggressive PCa drank more beer than patients with non-aggressive PCa (heavy, OR = 1.48, p = 0.013). Interestingly, heavy wine intake was inversely associated with PCa aggressiveness (OR = 0.56, p = 0.009). Conclusions: The intake patterns of some alcoholic beverage types differed by PCa status. Our findings can provide valuable information for developing custom alcohol interventions for PCa patients.

Published
2022

33. Author response for 'Prevalence and clinical prediction of mitochondrial disorders in a large neuropediatric cohort'

Author

Fanny Kortüm, Jessika Johannsen, Katja Kloth, Nadia Obi, Theresia Herget, Konstantinos Tsiakas, Christian Kubisch, Jonas Denecke, Matias Wagner, René Santer, Amelie T. Ven, Holger Prokisch, Tasja Scholz, Jasmin Lisfeld, Davor Lessel, Maja Hempel, Saskia B. Wortmann, and Tatjana Bierhals

Subjects
Pediatrics, medicine.medical_specialty, business.industry, Mitochondrial disease, Cohort, Medicine, business, medicine.disease
Published
2021

34. ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants

Author

Bernarda Lozić, Emilia K. Bijlsma, Janine Altmüller, Amelie T van der Ven, Julia Tagoe, Holger Thiele, Jonas Denecke, Davor Lessel, Katja Kloth, Ping Yee Billie Au, Mariëtte J.V. Hoffer, and Christian Kubisch

Subjects
0301 basic medicine, Ankyrins, Male, Adolescent, Autism Spectrum Disorder, Developmental delay, Mutation, Missense, Intellectual disability, Loss of Heterozygosity, Biology, Ankyrin-G, ANK3, Frameshift mutation, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Genetics, medicine, Missense mutation, Humans, Protein Isoforms, Child, Genetics (clinical), Loss function, Isoform-based phenotypic continuum, medicine.disease, Phenotype, Human genetics, Zygosity, 030104 developmental biology, Autism spectrum disorder, Neurodevelopmental Disorders, Original Article, Technology Platforms, 030217 neurology & neurosurgery
Abstract

ANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Here, we present four individuals affected by a variable neurodevelopmental phenotype harboring a heterozygous frameshift or nonsense variant affecting all ANK3 transcripts. Thus, we provide further evidence of an isoform-based phenotypic continuum underlying ANK3-associated pathologies and expand its phenotypic spectrum.

Published
2021

35. Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Author

Ian R. Berry, Martin R. Larsen, Ann M. Neumeyer, Lilian Bomme Ousager, Leah J. Rowe, Richard E. Person, Chanika Phornphutkul, David A. Koolen, Constance T. R. M. Stumpel, Konrad Platzer, Elizabeth J. Bhoj, Eric Chater-Diehl, Jason Bunn, Erika Leenders, Koen L.I. van Gassen, Joshua Charkow, Rosanna Weksberg, Ny Hoang, Roos Cuperus, Davor Lessel, Rolph Pfundt, Oana Caluseriu, Sarah J. Goodman, Leandra Folk, Fanggeng Zou, Michelle T. Siu, David Chitayat, Dmitrijs Rots, Jeroen R. Vermeulen, Shuxi Liu, Cheryl Cytrynbaum, Elin Tønne, Hein Brackel, Mareike Mertens, Jennifer Campbell, Jonathan B. Strober, Maja Hempel, Tjitske Kleefstra, Małgorzata J.M. Nowaczyk, Amy Crunk, Marta Pacio-Míguez, Fernando Santos-Simarro, Nicola Brunetti-Pierri, Christa de Geus, María Palomares-Bralo, Lisenka E.L.M. Vissers, Sander Pajusalu, Peter Kannu, Sanaa Choufani, Kristin Lindstrom, Margarita Saenz, Berkley Schmidt, Daniëlle G.M. Bosch, Han G. Brunner, Arie van Haeringen, Ellen van Binsbergen, Brianna Pruniski, Claudia A. L. Ruivenkamp, William G. Wilson, Servi J. C. Stevens, Susan Walker, Kristian Tveten, Zain Awamleh, Gerarda Cappuccio, Alexander J. M. Dingemans, Michael Kwint, Ebba Alkhunaizi, Jonas Denecke, Alyssa Ritter, Eric W. Klee, Bert B.A. de Vries, Jeske V.T. van Harssel, Stephen Meyn, A. Chantal Deden, Francisca Millan, Eva Morava, Ingrid M. Wentzensen, Anne Slavotinek, Stephen W. Scherer, Katrin Õunap, Tuula Rinne, Jessica A. Radley, Yili Xie, Thatjana Gardeitchik, Laura Schultz-Rogers, Karit Reinson, Ronald D. Cohn, Hui Yang, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, MUMC+: DA KG Lab Centraal Lab (9), Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: DA Klinische Genetica (5), Rots, Dmitrij, Chater-Diehl, Eric, Dingemans, Alexander J M, Goodman, Sarah J, Siu, Michelle T, Cytrynbaum, Cheryl, Choufani, Sanaa, Hoang, Ny, Walker, Susan, Awamleh, Zain, Charkow, Joshua, Meyn, Stephen, Pfundt, Rolph, Rinne, Tuula, Gardeitchik, Thatjana, de Vries, Bert B A, Deden, A Chantal, Leenders, Erika, Kwint, Michael, Stumpel, Constance T R M, Stevens, Servi J C, Vermeulen, Jeroen R, van Harssel, Jeske V T, Bosch, Danielle G M, van Gassen, Koen L I, van Binsbergen, Ellen, de Geus, Christa M, Brackel, Hein, Hempel, Maja, Lessel, Davor, Denecke, Jona, Slavotinek, Anne, Strober, Jonathan, Crunk, Amy, Folk, Leandra, Wentzensen, Ingrid M, Yang, Hui, Zou, Fanggeng, Millan, Francisca, Person, Richard, Xie, Yili, Liu, Shuxi, Ousager, Lilian B, Larsen, Martin, Schultz-Rogers, Laura, Morava, Eva, Klee, Eric W, Berry, Ian R, Campbell, Jennifer, Lindstrom, Kristin, Pruniski, Brianna, Neumeyer, Ann M, Radley, Jessica A, Phornphutkul, Chanika, Schmidt, Berkley, Wilson, William G, Õunap, Katrin, Reinson, Karit, Pajusalu, Sander, van Haeringen, Arie, Ruivenkamp, Claudia, Cuperus, Roo, Santos-Simarro, Fernando, Palomares-Bralo, María, Pacio-Míguez, Marta, Ritter, Alyssa, Bhoj, Elizabeth, Tønne, Elin, Tveten, Kristian, Cappuccio, Gerarda, Brunetti-Pierri, Nicola, Rowe, Leah, Bunn, Jason, Saenz, Margarita, Platzer, Konrad, Mertens, Mareike, Caluseriu, Oana, Nowaczyk, Małgorzata J M, Cohn, Ronald D, Kannu, Peter, Alkhunaizi, Ebba, Chitayat, David, Scherer, Stephen W, Brunner, Han G, Vissers, Lisenka E L M, Kleefstra, Tjitske, Koolen, David A, and Weksberg, Rosanna

Subjects
0301 basic medicine, Heart Septal Defects, Ventricular, Male, DNA methylation signature, nonsense-mediated decay, speech delay, PROTEIN, 030105 genetics & heredity, PHENOTYPE, epigenomic, Medical and Health Sciences, Epigenesis, Genetic, Craniofacial Abnormalities, Cohort Studies, Neurodevelopmental disorder, 2.1 Biological and endogenous factors, Aetiology, Genetics (clinical), Growth Disorders, Epigenomics, non-FLHS SRCAP-related NDD, Genetics, Adenosine Triphosphatases, Genetics & Heredity, neurodevelopmental disorders, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], SOTOS-LIKE, Biological Sciences, SRCAP, Hypotonia, AT-HOOK, 3. Good health, Phenotype, Mental Health, intellectual disability, Speech delay, DNA methylation, Female, medicine.symptom, Abnormalities, Multiple, EXON 34, Intellectual and Developmental Disabilities (IDD), Locus (genetics), Biology, genotype-phenotype correlation, DIAGNOSIS, Article, 03 medical and health sciences, Genetic, Clinical Research, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Floating-Harbor syndrome, SPECTRUM, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MUTATIONS, Heart Septal Defects, Infant, Newborn, Ventricular, dNaM, Infant, DNA Methylation, medicine.disease, Newborn, neurodevelopmental disorder, GENE, Brain Disorders, 030104 developmental biology, Floating–Harbor syndrome, Case-Control Studies, Mutation, epigenomics, EPISIGNATURES, Epigenesis
Abstract

Contains fulltext : 234078.pdf (Publisher’s version ) (Open Access) Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

Published
2021

36. The Discovery of a LEMD2-Associated Nuclear Envelopathy with Early Progeroid Appearance Suggests Advanced Applications for AI-Driven Facial Phenotyping

Author

Emanuela Scarano, Tomasz Stokowy, Tzung-Chien Hsieh, Florian Erger, Janine Altmueller, Christian Gilissen, Gunnar Houge, Trine Prescott, Christian Kubisch, Andrea Bevot, Maria Redfors, Davor Lessel, Laura Mazzanti, Torunn Fiskerstrand, Angelika Riess, Dejan Đukić, Peter Krawitz, Cecilie F. Rustad, Christian Netzer, Itamar Jobani, and Felix Marbach

Subjects
Male, 0301 basic medicine, Adolescent, Computational biology, Biology, 03 medical and health sciences, Progeria, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Artificial Intelligence, Report, Cell Line, Tumor, Genetics, medicine, Humans, Mass Screening, Supernumerary, Diagnosis, Computer-Assisted, Child, Gene, Genetics (clinical), Cell Nucleus, Genetic disorder, Membrane Proteins, Nuclear Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Geneticist, Fibroblasts, Prognosis, medicine.disease, Phenotype, 030104 developmental biology, Child, Preschool, Face, Mutation, Nuclear lamina, Intention tremor, medicine.symptom, Medical Informatics, 030217 neurology & neurosurgery
Abstract

Over a relatively short period of time, the clinical geneticist’s “toolbox” has been expanded by machine-learning algorithms for image analysis, which can be applied to the task of syndrome identification on the basis of facial photographs, but these technologies harbor potential beyond the recognition of established phenotypes. Here, we comprehensively characterized two individuals with a hitherto unknown genetic disorder caused by the same de novo mutation in LEMD2 (c.1436C>T;p.Ser479Phe), the gene which encodes the nuclear envelope protein LEM domain-containing protein 2 (LEMD2). Despite different ages and ethnic backgrounds, both individuals share a progeria-like facial phenotype and a distinct combination of physical and neurologic anomalies, such as growth retardation; hypoplastic jaws crowded with multiple supernumerary, yet unerupted, teeth; and cerebellar intention tremor. Immunofluorescence analyses of patient fibroblasts revealed mutation-induced disturbance of nuclear architecture, recapitulating previously published data in LEMD2-deficient cell lines, and additional experiments suggested mislocalization of mutant LEMD2 protein within the nuclear lamina. Computational analysis of facial features with two different deep neural networks showed phenotypic proximity to other nuclear envelopathies. One of the algorithms, when trained to recognize syndromic similarity (rather than specific syndromes) in an unsupervised approach, clustered both individuals closely together, providing hypothesis-free hints for a common genetic etiology. We show that a recurrent de novo mutation in LEMD2 causes a nuclear envelopathy whose prognosis in adolescence is relatively good in comparison to that of classical Hutchinson-Gilford progeria syndrome, and we suggest that the application of artificial intelligence to the analysis of patient images can facilitate the discovery of new genetic disorders.

Published
2019

37. Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study

Author

Jeri Kim, Jong Y. Park, Johanna Schleutker, Davor Lessel, Jie Zheng, Rebecca C Richmond, Lovise Maehle, J. Athene Lane, Barry S. Rosenstein, Ana Vega, Robert J. Hamilton, Kim De Ruyck, Richard M. Martin, Graham G. Giles, Sonja I. Berndt, Jyotsna Batra, Manuela Gago Dominguez, Freddie C. Hamdy, Radka Kaneva, Ali Amin Al Olama, Lisa A. Cannon-Albright, Ruth C. Travis, Susan M. Gapstur, Charleen D. Adams, Geraldine Cancel-Tassin, Stephen J. Chanock, Victoria L. Stevens, Lisa F. Newcomb, Diana L. Santos Ferreira, George Davey Smith, David E. Neal, Peter Würtz, Fredrick R. Schumacher, Henrik Grönberg, Manolis Kogevinas, Adam S. Kibel, Christopher A. Haiman, Florence Menegaux, Cezary Cybulski, Sue A. Ingles, Judith A. Clements, Lorelei A. Mucci, Børge G. Nordestgaard, Wes Spiller, Stella Koutros, Nora Pashayan, Karina Dalsgaard Sørensen, David V. Conti, Hardev Pandha, Rosalind A. Eeles, Kay-Tee Khaw, Vanessa Y Tan, Catharine M L West, Sara Benlloch, Christiane Maier, Jenny L Donovan, Azad Hassan Abdul Razack, Catherine M. Tangen, Nawaid Usmani, Yong-Jie Lu, Hermann Brenner, Zsofia Kote-Jarai, Paul A. Townsend, Frank Claessens, Kathryn L. Penney, Demetrius Albanes, Stephen N. Thibodeau, Fredrik Wiklund, Manuel R. Teixeira, Kenneth Muir, Janet L. Stanford, Monique J. Roobol, Susan L. Neuhausen, Alicja Wolk, Caroline L Relton, Esther M. John, and Urology

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, Epidemiology, BTC (Bristol Trials Centre), Article, Androgen deprivation therapy, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Prostate, Internal medicine, Mendelian randomization, medicine, Metabolome, Biomarkers, Tumor, Humans, Phospholipids, Triglycerides, Aged, business.industry, Case-control study, Cancer, Prostatic Neoplasms, Mendelian Randomization Analysis, Middle Aged, Prostate-Specific Antigen, medicine.disease, United Kingdom, 3. Good health, Prostate-specific antigen, 030104 developmental biology, medicine.anatomical_structure, Cholesterol, Centre for Surgical Research, 030220 oncology & carcinogenesis, Case-Control Studies, ICEP, business, Genome-Wide Association Study
Abstract

Background: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer–metabolite associations using two-sample Mendelian randomization (MR). Methods: The case–control portion of the study was conducted in nine UK centers with men ages 50–69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Results: Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. Conclusions: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. Impact: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

Published
2019

38. Author Correction: Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Author

Sara Benlloch, Roger L. Milne, Azad Hassan Abdul Razack, José Manuel Ruiz-Dominguez, Steven Joniau, Maria P. Silva, Martin Andreas Røder, Constance Turman, Anne-Maree Haynes, Jin Ling, Robert N. Hoover, Jong Y. Park, Johanna Schleutker, Brian E. Henderson, Amy Hutchinson, Stephanie J. Weinstein, Manolis Kogevinas, Melissa Papargiris, Monique J. Roobol, Gill Barnett, Wayne D. Tilley, Elio Riboli, Samantha E.T. Larkin, Melissa C. Southey, Michelle Guy, Jeanette T. Bensen, Henrik Grönberg, Fredrick R. Schumacher, Karina Dalsgaard Sørensen, Davor Lessel, Carin Cavalli-Bjoerkman, Tomislav Kuliš, Barry S. Rosenstein, Paula Kujala, Michael Davis, Andrzej M. Kierzek, Antonio Finelli, Gerald L. Andriole, Leire Moya, Antonio Gómez-Caamaño, Demetrius Albanes, Jianming Guo, Lisa F. Newcomb, Koveela Govindasami, Ji Lin, Gert De Meerleer, Manuel Luedeke, Richard M. Martin, Zeljko Kastelan, Kay-Tee Khaw, Ruth C. Travis, Rebecca Elliott, Alexandre R. Zlotta, Xin Guo, Kirsi Talala, Yangling Zhang, Lorelei A. Mucci, Marie Sanchez, Paul D.P. Pharoah, Mariona Bustamante, Peter Klarskov, Aleksandrina Vlahova, Srilakshmi Srinivasan, Aik T. Ong, David E. Neal, Sylvie Cénée, Esther M. John, Sonja I. Berndt, Kan Wang, Peter Iversen, Harry Ostrer, Michael Borre, Freddie C. Hamdy, Christopher A. Haiman, Ji Wu, Florence Menegaux, Jacek Marzec, Sara S. Strom, David P. Dearnaley, Jyotsna Batra, Piet Ost, Mariana C. Stern, Kim De Ruyck, Hyun Soo Park, Trina Yeadon, Elenko Popov, Yudong Wu, Svetlana Christova, Thomas Van den Broeck, Loic Le Marchand, Daniel J. Schaid, Babu Zachariah, Sune F. Nielsen, Mary-Anne Kedda, Judith A. Clements, Olivier Cussenot, Robert Szulkin, Shiro Saito, Andrew Evans, Douglas F. Easton, Gemma Castaño-Vinyals, Steve Hazel, Thérèse Truong, Guomin Wang, Katarina Cuk, Ants Toi, Rosalind A. Eeles, Darina Kachakova, Lourdes Mengual, Lisa G. Horvath, Yuan Chun Ding, Catharine M L West, Ana Carballo, Suzanne K. Chambers, Aurelie Vogt, Angela Cox, Daniel W. Lin, Dominika Wokołorczyk, Manuela Gago-Dominguez, Stephen J. Chanock, Federico Canzian, Aleksandra Klim, Tokhir Dadaev, Kathleen Herkommer, Tihomir Dikov, Lovise Maehle, Jasmine Lim, Janet L. Stanford, Martin Eklund, Guido Jenster, Soo-Hwang Teo, Teemu J. Murtola, Torben F. Ørntoft, Stella Koutros, Christa Stegmaier, Sofia Maia, Mitchell J. Machiela, Lisa A. Cannon-Albright, Clare Berry, Pamela Saunders, Lluís Cecchini, Jeri Kim, Radka Kaneva, Brigitte Trétarre, Anne George, Meir J. Stampfer, Marija Gamulin, Meng H. Tan, Angela Morgan, Jenny L Donovan, Graham G. Giles, Geraldine Cancel-Tassin, Neil Fleshner, Shannon K. McDonnell, Hardeep Ranu, Naomi Livni, Kimmo Taari, Sarah L. Kerns, Csilla Sipeky, Alicja Wolk, Edward Giovannucci, Ninghan Feng, Marta Cardoso, Jan-Erik Johansson, Catherine M. Tangen, Guangwen Cao, Adam S. Kibel, Robert J. MacInnis, Bernd Holleczek, Sarah J Lewis, Bo Zhou, Michael Broms, Maria Elena Martinez, Renea A. Taylor, Børge G. Nordestgaard, Fritz H. Schröder, Ali Amin Al Olama, Sue A. Ingles, Markus Aly, Jie Li, Lori S. Tillmans, Ana Vega, Patricia Calvo, Christopher J. Logothetis, David V. Conti, Miguel Aguado, Inés Gómez-Acebo, Tobias Nordström, Meiling Li, Elaine A. Ostrander, C.H. Bangma, Cyril Fisher, Joanne F. Aitken, Matthew Parliament, Gail P. Risbridger, John L. Hopper, Takashi Imai, Belynda Hicks, Victoria L. Stevens, Cezary Cybulski, G Marsden, Brian D. Carter, Vanessa M. Hayes, Nawaid Usmani, Vanio Mitev, Shan-Chao Zhao, Margaret Cook, Milan S. Geybels, Phyllis J. Goodman, Mark N. Brook, Nora Pashayan, Timothy J. Key, Yongwei Yu, Xavier Rebillard, David J. Hunter, Laura Fachal, Javier Llorca, Afshan Siddiq, Claire Aukim-Hastie, Trinidad Dierssen-Sotos, Walther Vogel, Angel Carracedo, Laura E. Beane Freeman, Julio M. Pow-Sang, Hardev Pandha, Robert A. Gardiner, Shaun M. Riska, Yong-Jie Lu, Zan Sun, Ramón Lobato-Busto, Ami Karlsson, Hongwei Zhang, Guoping Ren, Jing Ma, Huihai Wu, Søren M. Bentzen, John Pedersen, Claire Mulot, Girish S. Kulkarni, Jan Lubinski, Antonio Alcaraz, Jose E. Castelao, Athene Lane, Rasmus Bisbjerg, Thomas A. Sellers, Robert J. Hamilton, Jianfeng Xu, Sofie De Langhe, Artitaya Lophatananon, Maren Weisher, Agnieszka Michael, Yves Akoli Koudou, Niclas Håkansson, Alison M. Dunning, Hubert Thierens, Matthew L. Freedman, Kenneth Muir, Ian M. Thompson, Ian Whitmore, Susan L. Neuhausen, Chavdar Slavov, Wojciech Kluzniak, Laurence N. Kolonel, Lisa M. Butler, Teuvo L.J. Tammela, Alison Thwaites, Theodorus van der Kwast, Liesel M. FitzGerald, Thomas J. Schnoeller, Hermann Brenner, Christiane Maier, Amanda B. Spurdle, Jan Adolfsson, Atanaska Mitkova, Peter Kraft, Paula Peleteiro, Pär Stattin, Xin Sheng, Paul D. Brown, Ron H.N. van Schaik, Zsofia Kote-Jarai, Susan M. Gapstur, Paul A. Townsend, Edward J. Saunders, Bettina F. Drake, Stephen N. Thibodeau, Fredrik Wiklund, Paula Paulo, Esther Gracia-Lavedan, Xueying Mao, Marco Matejcic, Neil G. Burnet, A. L. Eckert, Manuel R. Teixeira, Sara Lindström, Weiyang He, Hui-Yi Lin, Suzanne Kolb, Linda Steele, Philipp Bohnert, Anssi Auvinen, Eli Marie Grindedal, Frank Claessens, and Kathryn L. Penney

Subjects
Urologic Diseases, 0301 basic medicine, Oncology, medicine.medical_specialty, Science, MEDLINE, General Physics and Astronomy, 02 engineering and technology, General Biochemistry, Genetics and Molecular Biology, Germline, 03 medical and health sciences, Internal medicine, medicine, PRACTICAL Consortium, lcsh:Science, Cancer, Prostate cancer risk, Multidisciplinary, business.industry, Prostate Cancer, Published Erratum, General Chemistry, 021001 nanoscience & nanotechnology, medicine.disease, Spelling, 3. Good health, 030104 developmental biology, Variation (linguistics), lcsh:Q, 0210 nano-technology, business
Abstract

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

39. Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Nghi Dang, Jonas Denecke, Jaclyn B. Murry, Laurence A. Bindoff, Tatjana Bierhals, Caroline Nava, Jordan H. Whitlock, Anne Slavotinek, Julian A. Martinez-Agosto, Frédéric Bilan, Ana Beleza-Meireles, Caroline Estes, Janneke H M Schuurs-Hoeijmakers, Adam Jackson, Christiane Zweier, David T. Miller, Kirsty McWalter, Gunnar Houge, Boris Keren, Jun Wang, Kinga K. Tomczak, Hans-Jürgen Kreienkamp, Siren Berland, Fabiola Quintero-Rivera, Charlotte A. Haaxma, Gwenaël Le Guyader, Laura Kellogg, Siddharth Banka, John M. Parant, Nan Cher Yeo, Jirat Chenbhanich, Davor Lessel, Cornelia Kraus, Yolanda Holler-Managan, Kelly Q. Minks, Julie Fleischer, Sarah F. Smithson, Geir J. Braathen, Ilaria Mannucci, Stanley F. Nelson, Trine Prescott, Luis F. Escobar, Simone F. Reiter, Kristian Tveten, David Bearden, Utz Fischer, Christian Kubisch, Perry B. Shieh, Jeff Abramson, Jane Juusola, Maja Hempel, Ulf W. Ljungblad, Daniel Groepper, Hannes Huber, Billur Moghaddam, Leslie Manace Brenman, Thorsten Althoff, Matthew Might, Alexander P.A. Stegmann, Cathy Kiraly-Borri, Øyvind L. Busk, Gareth Baynam, Hanitra Randrianaivo, Paul J. Benke, Farrah Rajabi, MUMC+: DA KG Lab Centraal Lab (9), and RS: FHML non-thematic output

Subjects
0301 basic medicine, INTELLECTUAL DISABILITY, Gene Expression, MEDICAL GENETICS, QH426-470, GUIDELINES, 0302 clinical medicine, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, 610 Medicine & health, Zebrafish, Genetics (clinical), Pediatric, Genetics, screening and diagnosis, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Immunohistochemistry, Phenotype, RNA Helicase A, Detection, Mental Health, Gene Knockdown Techniques, Medicine, Molecular Medicine, Medical genetics, Haploinsufficiency, RNA Helicases, STANDARDS, medicine.medical_specialty, Clinical Sciences, AMERICAN-COLLEGE, Biology, 03 medical and health sciences, Clinical Research, Molecular genetics, REVEALS, medicine, Animals, Humans, Genetic Predisposition to Disease, ddc:610, AUTISM, Molecular Biology, Germ-Line Mutation, Genetic Association Studies, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], IDENTIFICATION, MUTATIONS, Research, Prevention, biology.organism_classification, Human genetics, 4.1 Discovery and preclinical testing of markers and technologies, HEK293 Cells, 030104 developmental biology, Neurodevelopmental Disorders, Mutation, RNA HELICASE, Biomarkers, 030217 neurology & neurosurgery
Abstract

Background We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. Methods Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. Results We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. Conclusions Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.

Published
2021

40. Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Brian D. Carter, Gert De Meerleer, Michael B. Cook, Paul A. Townsend, Kim De Ruyck, Edward J. Saunders, Christopher A. Haiman, Atushi Takahashi, Sonja I. Berndt, Florence Menegaux, Cezary Cybulski, Barbara Nemesure, Loic Le Marchand, Sune F. Nielsen, Demetrius Albanes, Robert J. Hamilton, Ninghan Feng, Stella Koutros, Stephen J. Chanock, Wei Zheng, Thomas A. Sellers, Rick A. Kittles, Craig C. Teerlink, Stephen N. Thibodeau, Marija Gamulin, Artitaya Lophatananon, Niclas Håkansson, Fredrik Wiklund, Roberta McKean-Cowdin, Yuan Chun Ding, Nora Pashayan, Timothy J. Key, Børge G. Nordestgaard, Shannon K. McDonnell, Jong Y. Park, Laura Fachal, Martin Andreas Røder, Johanna Schleutker, Edward Giovannucci, Anssi Auvinen, Hardev Pandha, Maria Elena Martinez, Mitchell J. Machiela, Gill Barnett, Melissa C. Southey, Graham G. Giles, Barry S. Rosenstein, Stephen Watya, Bernd Holleczek, Pascal Blanchet, Agnieszka Michael, William J. Blot, James L. Mohler, Jack A. Taylor, Sarah L. Kerns, Adam S. Kibel, Piet Ost, Ana Vega, Richard M. Martin, Jennifer J. Hu, Nicholas Mancuso, Yukihide Momozawa, Robert J. MacInnis, Sue A. Ingles, Maureen Sanderson, Kai Uwe Saum, Markus Aly, Robert Szulkin, Davor Lessel, Hermann Brenner, Yves Akoli Koudou, Jan Lubinski, Mina Torres, Anselm Hennis, Eli Marie Grindedal, Csilla Sipeky, Susan L. Neuhausen, Alison M. Dunning, Alicja Wolk, Adam B. Murphy, Brandi Weaver, Mariana C. Stern, Paula Paulo, Stephanie J. Weinstein, Xueying Mao, Tobias Nordström, Neil Fleshner, Tokhir Dadaev, Teuvo L.J. Tammela, Jay H. Fowke, Tomislav Kuliš, Steven Joniau, Yudong Wu, Rosalind A. Eeles, Shan Chao Zhao, Kenneth Muir, Mark N. Brook, Hidewaki Nakagawa, Freddie C. Hamdy, Karina Dalsgaard Sørensen, Linda Steele, Alisha Chou, Dominika Wokołorczyk, Peggy Wan, Martin Eklund, Laurent Brureau, Lisa A. Cannon-Albright, Lilit C. Moss, Daniel J. Schaid, Luc Multigner, Benjamin A. Rybicki, Xin Sheng, Constance Turman, Ron H.N. van Schaik, Radka Kaneva, Zsofia Kote-Jarai, Frank Claessens, Katarina Cuk, Kay-Tee Khaw, Chad D. Huff, Henrik Grönberg, Kathryn L. Penney, Geraldine Cancel-Tassin, Eric A. Klein, Masashi Fujita, Jennifer Cullen, Michael Borre, Jenny L Donovan, Dana C. Crawford, Antonio Gómez-Caamaño, David V. Conti, Manuel Luedeke, Maya Ghoussaini, Janet L. Stanford, Peter Kraft, Ian M. Thompson, Koichi Matsuda, Soo-Hwang Teo, Christopher J. Logothetis, Robin J. Leach, Monique J. Roobol, Manuel R. Teixeira, Jose Esteban Castelao, Sara S. Strom, Vanio Mitev, Stig E. Bojesen, David J. Hunter, Wayne D. Tilley, Jyotsna Batra, Gerald L. Andriole, Christine Neslund-Dudas, Sara Lindström, Guido Jenster, Catherine M. Tangen, William S. Bush, Maren Weischer, Chavdar Slavov, Thomas J. Schnoeller, Javier Llorca, Claire Aukim-Hastie, Nawaid Usmani, Lisa G. Horvath, Daniel W. Lin, Esther M. John, Burcu F. Darst, Milan S. Geybels, Phyllis J. Goodman, Lynne R. Wilkens, Ali Amin Al Olama, Lorelei A. Mucci, Peter Iversen, Christiane Maier, Victoria L. Stevens, Andreia Brandão, Graham Casey, Neil G. Burnet, Ann W. Hsing, Hongwei Zhang, Laura E. Beane Freeman, Susan M. Gapstur, Sara Benlloch, James E. Mensah, Marie-Élise Parent, Jianfeng Xu, Bettina F. Drake, Jeannette T. Bensen, Azad Hassan Abdul Razack, Edward D. Yeboah, David E. Neal, John D. Carpten, Ruth C. Travis, Thomas J. Hoffmann, Thomas Van den Broeck, Jeri Kim, Ali Sahimi, Gemma Castaño-Vinyals, Alexander Lubwama, Leire Moya, Elio Riboli, Douglas F. Easton, Suzanne K. Chambers, Yong-Jie Lu, Melinda C. Aldrich, Manuela Gago-Dominguez, John S. Witte, Matthew Parliament, Gail P. Risbridger, Samantha E.T. Larkin, Lisa F. Newcomb, Fredrick R. Schumacher, Shiv Srivastava, Jasmine Lim, Meir J. Stampfer, Harry Ostrer, Judith A. Clements, Thérèse Truong, Catharine M L West, Zan Sun, Olivier Cussenot, Gyorgy Petrovics, Lovise Maehle, Elizabeth T. H. Fontham, William B. Isaacs, Hui Yi Lin, Rohit Varma, Elaine A. Ostrander, Manolis Kogevinas, Robert N. Hoover, Sandeep Singhal, Antonio Finelli, and Stephen K. Van Den Eeden

Subjects
0303 health sciences, business.industry, Published Erratum, MEDLINE, Genome-wide association study, Computational biology, Biology, medicine.disease, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Meta-analysis, Genetics, medicine, Susceptibility locus, 06 Biological Sciences, 11 Medical and Health Sciences, Personalized medicine, Genetic risk, business, 030217 neurology & neurosurgery, 030304 developmental biology, Developmental Biology
Abstract

In the version of this article originally published, the names of the equally contributing authors and jointly supervising authors were switched. The correct affiliations are: “These authors contributed equally: David V. Conti, Burcu F. Darst. These authors jointly supervised this work: David V. Conti, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman.” The error has been corrected in the HTML and PDF versions of the article.

Published
2021

41. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Paul A. Townsend, Edward J. Saunders, Hidewaki Nakagawa, Manuel R. Teixeira, Graham Casey, Demetrius Albanes, Christine Neslund-Dudas, Sara Lindström, William S. Bush, Maren Weischer, Lisa A. Cannon-Albright, Rick A. Kittles, Peggy Wan, Martin Eklund, Stephen N. Thibodeau, Burcu F. Darst, Fredrik Wiklund, Nicholas Mancuso, Jeri Kim, Jong Y. Park, Johanna Schleutker, Maureen Sanderson, Samantha E.T. Larkin, Radka Kaneva, Hongwei Zhang, Daniel J. Schaid, Luc Multigner, Marie-Élise Parent, Robert Szulkin, Fredrick R. Schumacher, Geraldine Cancel-Tassin, Jianfeng Xu, Gill Barnett, Melissa C. Southey, Yuan Chun Ding, Alexander Lubwama, Maria Elena Martinez, Manolis Kogevinas, Linda Steele, Laurent Brureau, Shiv Srivastava, Maya Ghoussaini, Alison M. Dunning, Adam B. Murphy, Kenneth Muir, Edward Giovannucci, Mitchell J. Machiela, James L. Mohler, Jack A. Taylor, Robert N. Hoover, Sandeep Singhal, Chavdar Slavov, Guido Jenster, Frank Claessens, Neil Fleshner, Sara Benlloch, Gert De Meerleer, Michael B. Cook, Zan Sun, Harry Ostrer, Pascal Blanchet, Lynne R. Wilkens, Ali Amin Al Olama, Sue A. Ingles, Markus Aly, Jay H. Fowke, Agnieszka Michael, Yves Akoli Koudou, Victoria L. Stevens, Kathryn L. Penney, Ana Vega, Xin Sheng, Ron H.N. van Schaik, Zsofia Kote-Jarai, Kim De Ruyck, Christopher A. Haiman, Atushi Takahashi, Florence Menegaux, Judith A. Clements, Stephen K. Van Den Eeden, Brian D. Carter, Wayne D. Tilley, Antonio Finelli, Jennifer J. Hu, Hermann Brenner, Thomas Van den Broeck, Shan Chao Zhao, Azad Hassan Abdul Razack, Edward D. Yeboah, Sonja I. Berndt, Barbara Nemesure, Mark N. Brook, David V. Conti, Katarina Cuk, Teuvo L.J. Tammela, Ali Sahimi, Stephen J. Chanock, Loic Le Marchand, Gemma Castaño-Vinyals, Sune F. Nielsen, Sara S. Strom, Ann W. Hsing, Roberta McKean-Cowdin, David J. Hunter, Ian M. Thompson, Børge G. Nordestgaard, Jyotsna Batra, Paula Paulo, Masashi Fujita, Jennifer Cullen, Susan M. Gapstur, Sarah L. Kerns, Lorelei A. Mucci, Neil G. Burnet, Xueying Mao, Hui Yi Lin, Rohit Varma, Marija Gamulin, Wei Zheng, Thomas A. Sellers, Adam S. Kibel, Robert J. Hamilton, Leire Moya, Ninghan Feng, Laura E. Beane Freeman, James E. Mensah, Catherine M. Tangen, Shannon K. McDonnell, Matthew Parliament, Davor Lessel, Gail P. Risbridger, Mina Torres, Janet L. Stanford, Bettina F. Drake, Soo-Hwang Teo, Robert J. MacInnis, Stig E. Bojesen, Jeannette T. Bensen, William J. Blot, Stella Koutros, Robin J. Leach, Graham G. Giles, Piet Ost, Artitaya Lophatananon, Laura Fachal, Tomislav Kuliš, Peter Kraft, Monique J. Roobol, Elaine A. Ostrander, Niclas Håkansson, Anselm Hennis, Yukihide Momozawa, Anssi Auvinen, Koichi Matsuda, Steven Joniau, Lisa G. Horvath, Javier Llorca, Claire Aukim-Hastie, Bernd Holleczek, Daniel W. Lin, Gerald L. Andriole, John D. Carpten, Eli Marie Grindedal, Rosalind A. Eeles, Elio Riboli, Constance Turman, Martin Andreas Røder, Yong-Jie Lu, Tobias Nordström, Kai Uwe Saum, Esther M. John, Melinda C. Aldrich, Peter Iversen, Henrik Grönberg, John S. Witte, Andreia Brandão, Eric A. Klein, Olivier Cussenot, Barry S. Rosenstein, Stephen Watya, Jan Lubinski, Douglas F. Easton, Dana C. Crawford, Gyorgy Petrovics, Thomas J. Schnoeller, Richard M. Martin, Stephanie J. Weinstein, Jose Esteban Castelao, Suzanne K. Chambers, Tokhir Dadaev, Karina Dalsgaard Sørensen, Antonio Gómez-Caamaño, Lisa F. Newcomb, Csilla Sipeky, Lovise Maehle, Brandi Weaver, Susan L. Neuhausen, Christiane Maier, Alicja Wolk, Vanio Mitev, Thérèse Truong, Manuel Luedeke, Jenny L Donovan, Mariana C. Stern, Catharine M L West, Manuela Gago-Dominguez, Elizabeth T. H. Fontham, William B. Isaacs, David E. Neal, Christopher J. Logothetis, Alisha Chou, Jasmine Lim, Benjamin A. Rybicki, Kay-Tee Khaw, Meir J. Stampfer, Chad D. Huff, Thomas J. Hoffmann, Michael Borre, Freddie C. Hamdy, Nawaid Usmani, Cezary Cybulski, Craig C. Teerlink, Milan S. Geybels, Nora Pashayan, Timothy J. Key, Phyllis J. Goodman, Hardev Pandha, Ruth C. Travis, Yudong Wu, Dominika Wokołorczyk, Lilit C. Moss, University of Southern California (USC), Keck School of Medicine [Los Angeles], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut de recherche en santé, environnement et travail (Irset), 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 ), CHU Pointe-à-Pitre/Abymes [Guadeloupe], The institute of cancer research [London], U01CA194393, National Institutes of Health, NA, Achievement Rewards for College Scientists Foundation, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-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 ), Urology, Clinical Chemistry, Darst, Burcu F [0000-0002-6205-4632], Chou, Alisha [0000-0001-7521-6373], Schumacher, Fredrick R [0000-0002-3073-7463], Dadaev, Tokhir [0000-0002-8268-0438], Brook, Mark N [0000-0002-8969-2378], Hoffmann, Thomas J [0000-0001-6893-4449], Takahashi, Atushi [0000-0001-7099-8767], Matsuda, Koichi [0000-0001-7292-2686], Fujita, Masashi [0000-0002-1457-6233], Muir, Kenneth [0000-0001-6429-988X], Stevens, Victoria L [0000-0003-0259-4407], Schleutker, Johanna [0000-0002-1863-0305], Sipeky, Csilla [0000-0002-8853-4722], Auvinen, Anssi [0000-0003-1125-4818], Giles, Graham G [0000-0003-4946-9099], Martin, Richard M [0000-0002-7992-7719], Nordestgaard, Børge G [0000-0002-1954-7220], Bojesen, Stig E [0000-0002-4061-4133], Røder, Martin Andreas [0000-0002-0019-5333], Batra, Jyotsna [0000-0003-4646-6247], Tilley, Wayne [0000-0003-1893-2626], Risbridger, Gail P [0000-0003-3089-4028], Gronberg, Henrik [0000-0002-1073-2753], Eklund, Martin [0000-0001-5032-5266], Nordström, Tobias [0000-0003-4915-7546], Pashayan, Nora [0000-0003-0843-2468], Dunning, Alison M [0000-0001-6651-7166], Travis, Ruth C [0000-0002-9571-0763], Riboli, Elio [0000-0001-6795-6080], Park, Jong Y [0000-0002-6384-6447], Weinstein, Stephanie J [0000-0002-3834-1535], Kraft, Peter [0000-0002-4472-8103], Ostrander, Elaine A [0000-0001-6075-9738], Wolk, Alicja [0000-0001-7387-6845], Håkansson, Niclas [0000-0001-7673-5554], Machiela, Mitchell J [0000-0001-6538-9705], Sørensen, Karina Dalsgaard [0000-0002-4902-5490], Zheng, Wei [0000-0003-1226-070X], Mensah, James E [0000-0003-4133-1722], Lu, Yong-Jie [0000-0001-6174-6621], West, Catharine ML [0000-0002-0839-3449], Cancel-Tassin, Géraldine [0000-0002-9583-6382], Truong, Thérèse [0000-0002-2943-6786], Vega, Ana [0000-0002-7416-5137], Gómez-Caamaño, Antonio [0000-0002-9773-4590], Fachal, Laura [0000-0002-7256-9752], Kerns, Sarah L [0000-0002-6503-0011], Ostrer, Harry [0000-0002-2209-5376], Teixeira, Manuel R [0000-0002-4896-5982], Brandão, Andreia [0000-0003-0938-1543], Cannon-Albright, Lisa [0000-0003-2602-3668], Multigner, Luc [0000-0003-3205-8568], Klein, Eric A [0000-0002-1783-0698], Murphy, Adam B [0000-0001-9977-3473], Michael, Agnieszka [0000-0002-7262-6227], Ost, Piet [0000-0002-2203-4848], Xu, Jianfeng [0000-0002-1343-8752], Teo, Soo-Hwang [0000-0002-0444-590X], Lessel, Davor [0000-0003-4496-244X], Kulis, Tomislav [0000-0002-0895-5691], Joniau, Steven [0000-0003-3195-9890], Bush, William S [0000-0002-9729-6519], Crawford, Dana C [0000-0002-6437-6248], Roobol, Monique J [0000-0001-6967-1708], Jenster, Guido [0000-0002-8658-2552], Van Den Eeden, Stephen K [0000-0002-5599-8387], Easton, Douglas F [0000-0003-2444-3247], Chanock, Stephen J [0000-0002-2324-3393], Wiklund, Fredrik [0000-0002-4623-0544], Eeles, Rosalind A [0000-0002-3698-6241], Haiman, Christopher A [0000-0002-0097-9971], and Apollo - University of Cambridge Repository

Subjects
Male, 8Q24, Genome-wide association study, Continental Population Groups/genetics, VARIANTS, Prostate cancer, 0302 clinical medicine, Risk Factors, Epidemiology, IMPUTATION, Odds Ratio, Prostatic Neoplasms/diagnosis, 0303 health sciences, education.field_of_study, Continental Population Groups, Manchester Cancer Research Centre, Middle Aged, Càncer--Aspectes genètics, 3. Good health, ODDS RATIOS, 06 Biological Sciences, 11 Medical and Health Sciences, medicine.medical_specialty, Population, Biology, prostate cancer, meta-analysis, SEQUENCE, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Genetics, medicine, BREAST-CANCER, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, education, 030304 developmental biology, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, MUTATIONS, ResearchInstitutes_Networks_Beacons/mcrc, Racial Groups, Prostatic Neoplasms, Molecular Sequence Annotation, Odds ratio, medicine.disease, BRCA2, Pròstata--Càncer, Genetic Loci, 030217 neurology & neurosurgery, Imputation (genetics), Genètica, Demography, Developmental Biology, Genome-Wide Association Study
Abstract

International audience; Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Published
2021

42. Prevalence and clinical prediction of mitochondrial disorders in a large neuropediatric cohort

Author

Holger Prokisch, Christian Kubisch, Maja Hempel, Jasmin Lisfeld, Tatjana Bierhals, Theresia Herget, Saskia B. Wortmann, René Santer, Fanny Kortüm, Amelie T van der Ven, Jessika Johannsen, Tasja Scholz, Matias Wagner, Jonas Denecke, Nadia Obi, Konstantinos Tsiakas, Davor Lessel, and Katja Kloth

Subjects
medicine.medical_specialty, Pediatrics, Mitochondrial Diseases, Genotype, Mitochondrial disease, Early detection, Disease, Cohort Studies, Child Development Disorders, Early Diagnosis, Medical Genetics, Mitochondria, Whole Exome Sequencing, Genetics, medicine, Prevalence, Humans, Genetic Predisposition to Disease, Child, Genetics (clinical), Exome sequencing, Alleles, Genetic Association Studies, business.industry, Incidence (epidemiology), Age Factors, medicine.disease, Prognosis, Genes, Mitochondrial, Phenotype, Cohort, Mutation, Medical genetics, Nervous System Diseases, Genetic diagnosis, business
Abstract

Neurological symptoms are frequent and often a leading feature of childhood-onset mitochondrial disorders (MD) but the exact incidence of MD in unselected neuropediatric patients is unknown. Their early detection is desirable due to a potentially rapid clinical decline and the availability of management options. In 491 children with neurological symptoms, a comprehensive diagnostic work-up including exome sequencing was performed. The success rate in terms of a molecular genetic diagnosis within our cohort was 51%. Disease-causing variants in a mitochondria-associated gene were detected in 12% of solved cases. In order to facilitate the clinical identification of MDs within neuropediatric cohorts, we have created an easy-to-use bedside-tool, the MDC-NP. In our cohort, the MDC-NP predicted disease conditions related to MDs with a sensitivity of 0.83, and a specificity of 0.96.

Published
2021

43. Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

Author

Christian Kubisch, Robert Rubinsztajn, Arianne Llamos Paneque, Philippe Manivet, Catarina Pereira, Laila Selim, Nathalie Escande-Beillard, Abigail Loh, Peter Bauer, Catherine Bartoli, Song-Hua Lee, Morgane Le Mao, Hϋlya Kayserili, Coraline Airault, Nihal M. Al Menabawy, Lisa Martino, Yosef Gruenbaum, Guy Lenaers, Antoine Muchir, Agnès Rötig, Annachiara De Sandre-Giovannoli, Nicolas Lévy, Sahar Elouej, Sheela Nampoothiri, Chayki Charar, Jean-François Deleuze, Karim Harhouri, Bruno Reversade, Davor Lessel, Geneviève Baujat, ACS - Heart failure & arrhythmias, 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), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Amrita Institute of Medical Sciences and Research Center, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Koç University, Cairo University Children Hospital, Medical Genetics Service Specialties Hospital, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hôpital Necker, The Hebrew University of Jerusalem (HUJ), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CENTOGENE AG, Institute of Medical Biology A*STAR, Sorbonne Université (SU), CeleScreen SAS, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), LENAERS, Guy, INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE - - Amidex2011 - ANR-11-IDEX-0001 - IDEX - VALID, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Escande-Beillard, Nathalie, Reversade, Bruno, Elouej,Sahar, Harhouri, Karim, Le Mao, Morgane, Baujat, Genevieve, Nampoothiri, Sheela, Menabawy, Nihal Al, Selim, Laila, Paneque, Arianne Llamos, Kubisch, Christian, Lessel, Davor, Rubinsztajn,Robert, Charar, Chayki, Bartoli, Catherine, Airault, Coraline, Deleuze, Jean-François, Rötig, Agnes, Bauer, Peter, Pereira, Catarina, Loh, Abigail, Muchir, Antoine, Martino, Lisa, Gruenbaum, Yosef, Lee, Song-Hua, Manivet, Philippe, Lenaers, Guy, Lévy, Nicolas, De Sandre-Giovannoli, Annachiara, and School of Medicine

Subjects
0301 basic medicine, Premature aging, Senescence, Pathology, medicine.medical_specialty, endocrine system, animal structures, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Apoptosis, General Biochemistry, Genetics and Molecular Biology, Progeroid syndromes, Article, Nuclear envelope, LMNA, 03 medical and health sciences, 0302 clinical medicine, Mitophagy, Genetics research, medicine, lcsh:Science, Multidisciplinary, business.industry, Glomerulosclerosis, General Chemistry, Energy metabolism, medicine.disease, 3. Good health, Mandibuloacral dysplasia, [SDV] Life Sciences [q-bio], 030104 developmental biology, Mitochondrial Membrane Protein, Next-generation sequencing, Medicine, lcsh:Q, business, 030217 neurology & neurosurgery
Abstract

Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients’ primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients’ fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features., Association Française contre les Myopathies (AFM); Deutsche Forschungsgemeinschaft; GENMED Laboratory of Excellence on Medical Genomics, Agence Nationale de la Recherche; Institut National de la Santé et de la Recherche Médicale (INSERM); Aix-Marseille University (AMU) by the RAREMED Amidex Project

Published
2020

44. Germline AGO2 mutations impair RNA interference and human neurological development

Author

Ee-Shien Tan, John Pappas, Tiffany Busa, Marjolein H. Willemsen, Erica H. Gerkes, Astrid Bruckmann, Linda Ramsdell, Davor Lessel, Chieko Chijiwa, Diana Mitter, Ghayda M. Mirzaa, Peter Ian Andrews, Daniela M. Zeitler, Claudia Schob, Pankaj Prasun, M. E. Suzanne Lewis, Rami Abou Jamra, Andriy Kazantsev, Aida Telegrafi, Steffen Syrbe, Chantal Missirian, Victoria Martens, Kimberly Foss, Margot R.F. Reijnders, Bianca Panis, Ilaria Mannucci, Bernarda Lozić, Fatemeh Hassani Nia, Rolph Pfundt, Tanja Kovacevic, Han G. Brunner, Christian Kubisch, Allyn McConkie-Rosell, Breana Cham, Gunter Meister, Jessika Johannsen, Veronika Graus, Henny H. Lemmink, Stefan Kindler, Jonas Denecke, Kirsty McWalter, Ivana Lessel, Zoya Ignatova, Hans-Jürgen Kreienkamp, Matthew Osmond, Thatjana Gardeitchik, Alexander P.A. Stegmann, Rachel Rabin, Alexander Bartholomäus, Jérémie Mortreux, Katharina Löhner, Tony Roscioli, Tjitske Kleefstra, Taila Hartley, Andreas Merkenschlager, Patrick Rump, Marie T. McDonald, Kym M. Boycott, Evelien Zonneveld-Huijssoon, David A. Dyment, Carey-Anne Evans, Margje Sinnema, Sabine Lüttgen, Joanna Lazier, Diana Le Duc, Kerith-Rae Dias, Ene-Choo Tan, 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), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-17-CE16-0025,MicroRNAct,Identification de complexes microARN/mARN fonctionnels dans le cerveau antérieur de souris: de la neurogenèse au comportement et à la pathologie(2017), MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output

Subjects
0301 basic medicine, INTELLECTUAL DISABILITY, MICRORNAS, [SDV]Life Sciences [q-bio], molecular-dynamics, General Physics and Astronomy, ARGONAUTE-2, ARGONAUTE-2, Hippocampus, Nervous System, Transcriptome, Mice, 0302 clinical medicine, RNA interference, Cluster Analysis, Phosphorylation, RNA, Small Interfering, lcsh:Science, Child, Regulation of gene expression, Neurons, Multidisciplinary, Molecular medicine, Neurodevelopmental disorders, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], 3. Good health, Cell biology, Child, Preschool, Argonaute Proteins, RNA Interference, STRUCTURAL BASIS, Adolescent, Science, Biology, Molecular Dynamics Simulation, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Protein Domains, microRNA, Gene silencing, Animals, Humans, RNA-Induced Silencing Complex, Gene Silencing, RNA, Messenger, Messenger RNA, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CLEAVAGE, HEK 293 cells, RECOGNITION, crystal-structure, RNA, General Chemistry, Dendrites, Fibroblasts, GENE, Rats, 030104 developmental biology, Germ Cells, HEK293 Cells, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, lcsh:Q, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development., AGO2 binds to miRNAs to repress expression of cognate target mRNAs. Here the authors report that heterozygous AGO2 mutations result in defects in neurological development and impair RNA interference.

Published
2020

45. Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Alexander P.A. Stegmann, Jun Wang, Anne Slavotinek, Cornelia Kraus, Paul J. Benke, Christiane Zweier, Fabiola Quintero-Rivera, Øyvind L. Busk, Kirsty McWalter, Hans-Jürgen Kreienkamp, Luis F. Escobar, Geir J. Braathen, Kristian Tveten, Farrah Rajabi, Charlotte A. Haaxma, David Bearden, John M. Parant, Yolanda Holler-Managan, Nghi Dang, Leslie Manace Brenman, Ana Beleza, Thorsten Althoff, Cathy Kiraly-Borri, Maja Hempel, Christian Kubisch, Kelly Q. Minks, Laura Kellogg, Hannes Huber, Ulf W. Ljungblad, Hanitra Randrianaivo, Perry B. Shieh, Jeff Abramson, Jirat Chenbhanich, Jonas Denecke, Billur Moghaddam, Gareth Baynam, Kinga K. Tomczak, Matthew Might, Jane Juusola, Jordan H. Whitlock, Gunnar Houge, Julie Fleischer, Laurence A. Bindoff, Siren Berland, Tatjana Bierhals, Adam Jackson, Gwenaël Le Guyader, Stanley F. Nelson, Caroline Estes, Nan Cher Yeo, Simone F. Reiter, Utz Fischer, Sarah F. Smithson, Daniel Groepper, Siddharth Banka, Davor Lessel, Frédéric Bilan, Ilaria Mannucci, Trine Prescott, David T. Miller, Janneke H M Schuurs-Hoeijmakers, Boris Keren, Jaclyn B. Murry, Caroline Nava, and Julian A. Martinez-Agosto

Subjects
Genetics, medicine.medical_specialty, biology, medicine.disease, biology.organism_classification, RNA Helicase A, Phenotype, Neurodevelopmental disorder, Molecular genetics, medicine, Missense mutation, Global developmental delay, Haploinsufficiency, Zebrafish
Abstract

BackgroundWe aimed to define the clinical and mutational spectrum, and to provide novel molecular insights into DHX30-associated neurodevelopmental disorder.MethodsClinical and genetic data from affected individuals were collected through family support group, GeneMatcher and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays.ResultsWe identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual bearing a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location and type we establish two distinct clinical subtypes. DHX30 loss-of-function mutations cause a milder phenotype whereas a severe phenotype is caused by HCM missense mutations that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of function with respect to SG formation. Behavioral characterization of dhx30 deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype.ConclusionsOur study highlights the usefulness of social media in order to define novel Mendelian disorders, and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories and research laboratories.

Published
2020

46. The

Author

Andreia, Brandão, Paula, Paulo, Sofia, Maia, Manuela, Pinheiro, Ana, Peixoto, Marta, Cardoso, Maria P, Silva, Catarina, Santos, Rosalind A, Eeles, Zsofia, Kote-Jarai, Kenneth, Muir, Ukgpcs Collaborators, Johanna, Schleutker, Ying, Wang, Nora, Pashayan, Jyotsna, Batra, Apcb BioResource, Henrik, Grönberg, David E, Neal, Børge G, Nordestgaard, Catherine M, Tangen, Melissa C, Southey, Alicja, Wolk, Demetrius, Albanes, Christopher A, Haiman, Ruth C, Travis, Janet L, Stanford, Lorelei A, Mucci, Catharine M L, West, Sune F, Nielsen, Adam S, Kibel, Olivier, Cussenot, Sonja I, Berndt, Stella, Koutros, Karina Dalsgaard, Sørensen, Cezary, Cybulski, Eli Marie, Grindedal, Jong Y, Park, Sue A, Ingles, Christiane, Maier, Robert J, Hamilton, Barry S, Rosenstein, Ana, Vega, The Impact Study Steering Committee And Collaborators, Manolis, Kogevinas, Fredrik, Wiklund, Kathryn L, Penney, Hermann, Brenner, Esther M, John, Radka, Kaneva, Christopher J, Logothetis, Susan L, Neuhausen, Kim De, Ruyck, Azad, Razack, Lisa F, Newcomb, Canary Pass Investigators, Davor, Lessel, Nawaid, Usmani, Frank, Claessens, Manuela, Gago-Dominguez, Paul A, Townsend, Monique J, Roobol, The Profile Study Steering Committee, The Practical Consortium, and Manuel R, Teixeira

Subjects
founder variant, cancer predisposition, prostate cancer, Article, CHEK2
Abstract

Simple Summary It is well-recognised the strong contribution of genetic factors to prostate cancer (PrCa) susceptibility, thus genetic screening is critical for presymptomatic diagnosis and identification of individuals at high-risk. In this context, recurrent founder variants in cancer predisposing genes, by providing specific targets for early identification of carriers at risk of developing the disease, may be leveraged to implement cost-efficient targeted genetic screening strategies. The goal of this study was to investigate whether CHEK2 c.349A>G, the only recurrent “likely pathogenic” variant in CHEK2 gene reported in the Portuguese population, plays an important role in PrCa development, and the possibility of a founder effect behind its origin. Our results clearly demonstrate that c.349A>G in the CHEK2 tumour-suppressor gene is a founder variant significantly associated with an increased risk of PrCa, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families. Abstract The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case–control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1–3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.

Published
2020

47. Identification of 22 susceptibility loci associated with testicular germ cell tumors

Author

Mingyao Li, Chey Loveday, Tongzhang Zheng, Chu Chen, Paloma Martin-Gimeno, Mark H. Greene, Javier Benitez, Stephen J. Chanock, Coby Meijer, Daphne Yang, Christopher D. Brown, Thorunn Rafnar, Lorenzo Richiardi, Marija Gamulin, Kari Stefansson, Michelle A.T. Hildebrandt, Matthew E. Johnson, Shweta Ramdas, Jourik A. Gietema, David J. Vaughn, Kevin T. Nead, Robert Karlsson, Struan F.A. Grant, Peter A. Kanetsky, Kristian Almstrup, David I. Quinn, Katherine L. Nathanson, Kurt D'Andrea, D. Timothy Bishop, Andrew D. Wells, Nandita Mitra, Katherine A. McGlynn, Jennifer T. Loud, Carlo Foresta, Lynn Anson-Cartwright, Jérémie Nsengimana, Alberto Ferlin, Lambertus A. Kiemeney, Rolf Inge Skotheim, Victoria K. Cortessis, Xifeng Wu, Chiara Grasso, Ragnhild A. Lothe, Tom Grotmol, Russ Hauser, Trine B. Haugen, Fredrik Wiklund, Clare Turnbull, Benita Weathers, Louise C. Pyle, Robert J. Hamilton, Stephen M. Schwartz, Davor Lessel, John Pluta, Ewa Rajpert-De Meyts, Rona Wilf, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Damage and Repair in Cancer Development and Cancer Treatment (DARE)

Subjects
Oncology, Male, Linkage disequilibrium, Somatic cell, General Physics and Astronomy, Genome-wide association study, Disease, VARIANTS, DMRT1, Linkage Disequilibrium, Neoplasms, Germ Cell and Embryonal / metabolism, Cell Line, Tumor, Chromosome Mapping, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Neoplasms, Germ Cell and Embryonal, Protein Interaction Maps, Testicular Neoplasms, Polymorphism, Single Nucleotide, Testicular Neoplasms / genetics, 0302 clinical medicine, Gene Regulatory Networks / genetics, Neoplasms, Medicine, FAMILIAL RISK, Cancer genetics, Genome-Wide Association Study / methods, 0303 health sciences, Tumor, Multidisciplinary, testicular germ cell tumors (TGCT), Protein Interaction Maps / genetics, Single Nucleotide, CANCER, medicine.anatomical_structure, SINGLE, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, CENP-I, Germ cell, endocrine system, medicine.medical_specialty, Science, GENOTYPE IMPUTATION, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Testicular cancer, Internal medicine, Neoplasms, Germ Cell and Embryonal / genetics, Polymorphism, GENOME-WIDE ASSOCIATION, METAANALYSIS, 030304 developmental biology, Genetic association study, business.industry, Cancer, General Chemistry, medicine.disease, Genetic Predisposition to Disease / genetics, BAX, Germ Cell and Embryonal, Testicular Neoplasms / metabolism, business
Abstract

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation., Testicular germ cell tumors are highly heritable, and the authors present the largest genome association study, identifying 22 novel loci, which account for a third of those identified to date. Implicated pathways include male germ cell development and differentiation, and chromosomal segregation.

Published
2020

48. Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations

Author

Rosalind A. Eeles, Anne van Altena, Rüdiger Klapdor, Rayjean J. Hung, Graham G. Giles, Ingo B. Runnebaum, Stacey J. Winham, Alicia Beeghly-Fadiel, Michelle A.T. Hildebrandt, Ruea-Yea Huang, Amanda B. Spurdle, Ahmad Alsulimani, Robert Winqvist, Robert J. Hamilton, Clare Turnbull, James M. Flanagan, Jan Gawełko, Kenneth Muir, Peter Kraft, Joseph Vijai, Anna Jakubowska, Paul D.P. Pharoah, Stephen J. Chanock, Ailith Ewing, Mary B. Daly, Artitaya Lophatananon, Arvids Irmejs, Hiltrud Brauch, Paolo Radice, Camilla Krakstad, Liher Imaz, Lambertus A. Kiemeney, Clara Bodelon, Nadeem Siddiqui, Alvaro N.A. Monteiro, Bozena Konopka, Taymaa May, Herbert Yu, Stefanie Burghaus, Michael E. Carney, Siddhartha Kar, Beata Spiewankiewicz, Fernando Moreno Antón, Andreas du Bois, Sune F. Nielsen, Ian Tomlinson, Elza Khusnutdinova, Paolo Peterlongo, Zhihua Chen, Deborah J. Thompson, Agnieszka Podgorski, Päivi Kannisto, Andrew Berchuck, Jenny Chang-Claude, Susan J. Ramus, Florian Heitz, Nawaid Usmani, Tracy A. O'Mara, Joellen M. Schildkraut, Jennifer Permuth, Beth Y. Karlan, Ignace Vergote, Douglas F. Easton, Sara Lindstroem, Agnieszka Mieszkowska, Kirsten B. Moysich, Ana Vega-Gliemmo, Simon A. Gayther, Arif B. Ekici, Lukasz Szafron, Kunle Odunsi, Marjanka K. Schmidt, Harvey A. Risch, Linda J. Titus, Weiva Sieh, Robert A. Vierkant, Davor Lessel, Line Bjørge, Allan Jensen, Wei Zheng, Holly R. Harris, Petra Kleiblova, Peter A. Fasching, Jonathan Tyrer, Iwona K. Rzepecka, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Susanne K. Kjaer, Esther M. John, Daniele Campa, Veronica Wendy Setiawan, Martin Koebel, Cheryl L. Thompson, Håkan Olsson, Dylan M. Glubb, Peter Hillemanns, and Kate Lawrenson

Subjects
Oncology, medicine.medical_specialty, Endometrial cancer, Cancer susceptibility, Susceptibility gene, Effective sample size, Biology, medicine.disease, Genome, medicine.anatomical_structure, Prostate, Internal medicine, medicine, Genetic association
Abstract

We report a meta-analysis of breast, prostate, ovarian, and endometrial cancer genome-wide association data (effective sample size: 237,483 cases/317,006 controls). This identified 465 independent lead variants (P−8) across 192 genomic regions. Four lead variants were >1Mb from previously identified risk loci for the four cancers and an additional 23 lead variant-cancer associations were novel for one of the cancers. Bayesian models supported pleiotropic effects involving at least two cancers at 222/465 lead variants in 118/192 regions. Gene-level association analysis identified 13 shared susceptibility genes (P−6) in 13 regions not previously implicated in any of the four cancers and not uncovered by our variant-level meta-analysis. Several lead variants had opposite effects across cancers, including a cluster of such variants in the TP53 pathway. Fifty-four lead variants were associated with blood cell traits and suggested genetic overlaps with clonal hematopoiesis. Our study highlights the remarkable pervasiveness of pleiotropy across hormone-related cancers, further illuminating their shared genetic and mechanistic origins at variant- and gene-level resolution.

Published
2020

49. Histone H3.3 beyond cancer: Germline mutations in

Author

Laura, Bryant, Dong, Li, Samuel G, Cox, Dylan, Marchione, Evan F, Joiner, Khadija, Wilson, Kevin, Janssen, Pearl, Lee, Michael E, March, Divya, Nair, Elliott, Sherr, Brieana, Fregeau, Klaas J, Wierenga, Alexandrea, Wadley, Grazia M S, Mancini, Nina, Powell-Hamilton, Jiddeke, van de Kamp, Theresa, Grebe, John, Dean, Alison, Ross, Heather P, Crawford, Zoe, Powis, Megan T, Cho, Marcia C, Willing, Linda, Manwaring, Rachel, Schot, Caroline, Nava, Alexandra, Afenjar, Davor, Lessel, Matias, Wagner, Thomas, Klopstock, Juliane, Winkelmann, Claudia B, Catarino, Kyle, Retterer, Jane L, Schuette, Jeffrey W, Innis, Amy, Pizzino, Sabine, Lüttgen, Jonas, Denecke, Tim M, Strom, Kristin G, Monaghan, Zuo-Fei, Yuan, Holly, Dubbs, Renee, Bend, Jennifer A, Lee, Michael J, Lyons, Julia, Hoefele, Roman, Günthner, Heiko, Reutter, Boris, Keren, Kelly, Radtke, Omar, Sherbini, Cameron, Mrokse, Katherine L, Helbig, Sylvie, Odent, Benjamin, Cogne, Sandra, Mercier, Stephane, Bezieau, Thomas, Besnard, Sebastien, Kury, Richard, Redon, Karit, Reinson, Monica H, Wojcik, Katrin, Õunap, Pilvi, Ilves, A Micheil, Innes, Kristin D, Kernohan, Gregory, Costain, M Stephen, Meyn, David, Chitayat, Elaine, Zackai, Anna, Lehman, Hilary, Kitson, Martin G, Martin, Julian A, Martinez-Agosto, Stan F, Nelson, Christina G S, Palmer, Jeanette C, Papp, Neil H, Parker, Janet S, Sinsheimer, Eric, Vilain, Jijun, Wan, Amanda J, Yoon, Allison, Zheng, Elise, Brimble, Giovanni Battista, Ferrero, Francesca Clementina, Radio, Diana, Carli, Sabina, Barresi, Alfredo, Brusco, Marco, Tartaglia, Jennifer Muncy, Thomas, Luis, Umana, Marjan M, Weiss, Garrett, Gotway, K E, Stuurman, Michelle L, Thompson, Kirsty, McWalter, Constance T R M, Stumpel, Servi J C, Stevens, Alexander P A, Stegmann, Kristian, Tveten, Arve, Vøllo, Trine, Prescott, Christina, Fagerberg, Lone Walentin, Laulund, Martin J, Larsen, Melissa, Byler, Robert Roger, Lebel, Anna C, Hurst, Joy, Dean, Samantha A, Schrier Vergano, Jennifer, Norman, Saadet, Mercimek-Andrews, Juanita, Neira, Margot I, Van Allen, Nicola, Longo, Elizabeth, Sellars, Raymond J, Louie, Sara S, Cathey, Elly, Brokamp, Delphine, Heron, Molly, Snyder, Adeline, Vanderver, Celeste, Simon, Xavier, de la Cruz, Natália, Padilla, J Gage, Crump, Wendy, Chung, Benjamin, Garcia, Hakon H, Hakonarson, and Elizabeth J, Bhoj

Subjects
endocrine system, SciAdv r-articles, Forkhead Transcription Factors, Neurodegenerative Diseases, Zebrafish Proteins, Histones, fluids and secretions, mental disorders, Genetics, Animals, Humans, Molecular Biology, reproductive and urinary physiology, Germ-Line Mutation, Zebrafish, Research Articles, Research Article
Abstract

Germ line mutations in H3F3A and H3F3B cause a previously unidentified neurodevelopmental syndrome., Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.

Published
2020

50. MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis

Author

Géraldine Viot, Sara Halbach, Sandra Yang, William T. Gibson, Megan T. Cho, Sabine Luettgen, Pierre-Marie Martin, Karen W. Gripp, Christopher T. Gordon, Michael J. Bamshad, Jonas Denecke, Benjamin Apple, Thierry Bienvenu, William B. Dobyns, Elizabeth Francisco, Jill R. Murrell, Deborah A. Nickerson, Nadja Ehmke, Angela E. Lin, Kelly Radtke, Lisenka E.L.M. Vissers, Shelagh Joss, Farah R. Zahir, Louise Amlie-Wolf, Francisca Millan, Joan M. Stoler, Michael Parker, Youngha Lee, Carey McDougall, Denise Horn, Ruth McGowan, Elaine H. Zackai, Nicolas Lebrun, Ingrid M. Wentzensen, Zöe Powis, Oliver Puk, Nancy Vegas, Dan Doherty, Noa Lev-El, Amanda Barone Pritchard, Joseph T. Shieh, Francesca Filippini, Mariëtte J.V. Hoffer, Russell R. Reid, Valérie Cormier-Daire, Murim Choi, Michele G. Mehaffey, Stanislas Lyonnet, Jan M. Friedman, Sarina G. Kant, Yuri A. Zarate, David Viskochil, Gordon K.C. Leung, Angela M. Kaindl, Steven L.C. Pei, Christopher C.Y. Mak, Clémantine Dimartino, Koenraad Devriendt, Tiong Yang Tan, Mullin H.C. Yu, Chumei Li, Brian H.Y. Chung, Tim M. Strom, Lindsay B. Henderson, Elliot S. Stolerman, Trevor L Hoffman, Lina Basel-Salmon, Davor Lessel, Chelsea Roadhouse, Gisele E. Ishak, Caitlin Troyer, Jong-Hee Chae, Claudia Gonzaga-Jauregui, Ann Seman, Naama Orenstein, Marcie A. Steeves, Eric G. Bend, James D. Weisfeld-Adams, Jamel Chelly, William G. Wilson, Jeanne Amiel, and Darrel Waggoner

Subjects
0301 basic medicine, Proband, Biology, 03 medical and health sciences, Exon, 0302 clinical medicine, Intellectual disability, medicine, Craniofacial, Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MN1, rhombencephalosynapsis, Original Articles, Perisylvian polymicrogyria, medicine.disease, craniofacial development, MCTT syndrome, 030104 developmental biology, medicine.anatomical_structure, intellectual disability, Cerebellar vermis, Trigeminal artery, Neurology (clinical), Haploinsufficiency, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 218289.pdf (Publisher’s version ) (Closed access) MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

Published
2020

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