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125 results on '"Sébastien Küry"'

1. Sex hormones and risk of lung and colorectal cancers in women: a Mendelian randomization study

Author: Marion Denos, Yi-Qian Sun, Ben Michael Brumpton, Yafang Li, Demetrius Albanes, Andrea Burnett-Hartman, Peter T. Campbell, Sébastien Küry, Christopher I. Li, Emily White, Jewel N. Samadder, Mark A. Jenkins, and Xiao-Mei Mai
Subjects: Colorectal cancer, Estradiol, HUNT, Lung cancer, Mendelian randomization, Sex hormones, Medicine, Science
Abstract: Abstract The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies on sex hormones and from the Trøndelag Health Study (HUNT) and large consortia on cancers. There was suggestive evidence of 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio 0.60, 95% confidence interval 0.37–0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.
Published: 2024
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2. Understanding neurodevelopmental proteasomopathies as new rare disease entities: A review of current concepts, molecular biomarkers, and perspectives

Author: Silvestre Cuinat, Stéphane Bézieau, Wallid Deb, Sandra Mercier, Virginie Vignard, Bertrand Isidor, Sébastien Küry, and Frédéric Ebstein
Subjects: Biomarkers, Loss-of-function variants, Neurodevelopmental disorders, Proteasome, Rare diseases, Therapeutic targets, Medicine (General), R5-920, Genetics, QH426-470
Abstract: The recent advances in high throughput sequencing technology have drastically changed the practice of medical diagnosis, allowing for rapid identification of hundreds of genes causing human diseases. This unprecedented progress has made clear that most forms of intellectual disability that affect more than 3% of individuals worldwide are monogenic diseases. Strikingly, a substantial fraction of the mendelian forms of intellectual disability is associated with genes related to the ubiquitin-proteasome system, a highly conserved pathway made up of approximately 1200 genes involved in the regulation of protein homeostasis. Within this group is currently emerging a new class of neurodevelopmental disorders specifically caused by proteasome pathogenic variants which we propose to designate “neurodevelopmental proteasomopathies”. Besides cognitive impairment, these diseases are typically associated with a series of syndromic clinical manifestations, among which facial dysmorphism, motor delay, and failure to thrive are the most prominent ones. While recent efforts have been made to uncover the effects exerted by proteasome variants on cell and tissue landscapes, the molecular pathogenesis of neurodevelopmental proteasomopathies remains ill-defined. In this review, we discuss the cellular changes typically induced by genomic alterations in proteasome genes and explore their relevance as biomarkers for the diagnosis, management, and potential treatment of these new rare disease entities.
Published: 2024
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3. LARP1 haploinsufficiency is associated with an autosomal dominant neurodevelopmental disorder

Author: James Chettle, Raymond J. Louie, Olivia Larner, Robert Best, Kevin Chen, Josephine Morris, Zinaida Dedeic, Anna Childers, R. Curtis Rogers, Barbara R. DuPont, Cindy Skinner, Sébastien Küry, Kevin Uguen, Marc Planes, Danielle Monteil, Megan Li, Aviva Eliyahu, Lior Greenbaum, Nofar Mor, Thomas Besnard, Bertrand Isidor, Benjamin Cogné, Alyssa Blesson, Anne Comi, Ingrid M. Wentzensen, Blake Vuocolo, Seema R. Lalani, Roberta Sierra, Lori Berry, Kent Carter, Stephan J. Sanders, and Sarah P. Blagden
Subjects: LARP1, autism, ASD, NDD, neurodevelopmental, metabolism, Genetics, QH426-470
Abstract: Summary: Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.
Published: 2024
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4. Exploring the origins of neurodevelopmental proteasomopathies associated with cardiac malformations: are neural crest cells central to certain pathological mechanisms?

Author: Virginie Vignard, Alban-Elouen Baruteau, Bérénice Toutain, Sandra Mercier, Bertrand Isidor, Richard Redon, Jean-Jacques Schott, Sébastien Küry, Stéphane Bézieau, Anne H. Monsoro-Burq, and Frédéric Ebstein
Subjects: neurodevelopmental proteasomopathies, cardiac malformations, craniofacial anomalies, neural crest cells, protein homeostasis, compensatory pathways, Biology (General), QH301-705.5
Abstract: Neurodevelopmental proteasomopathies constitute a recently defined class of rare Mendelian disorders, arising from genomic alterations in proteasome-related genes. These alterations result in the dysfunction of proteasomes, which are multi-subunit protein complexes essential for maintaining cellular protein homeostasis. The clinical phenotype of these diseases manifests as a syndromic association involving impaired neural development and multisystem abnormalities, notably craniofacial anomalies and malformations of the cardiac outflow tract (OFT). These observations suggest that proteasome loss-of-function variants primarily affect specific embryonic cell types which serve as origins for both craniofacial structures and the conotruncal portion of the heart. In this hypothesis article, we propose that neural crest cells (NCCs), a highly multipotent cell population, which generates craniofacial skeleton, mesenchyme as well as the OFT of the heart, in addition to many other derivatives, would exhibit a distinctive vulnerability to protein homeostasis perturbations. Herein, we introduce the diverse cellular compensatory pathways activated in response to protein homeostasis disruption and explore their potential implications for NCC physiology. Altogether, the paper advocates for investigating proteasome biology within NCCs and their early cranial and cardiac derivatives, offering a rationale for future exploration and laying the initial groundwork for therapeutic considerations.
Published: 2024
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5. Genome-wide interaction study of dietary intake of fibre, fruits, and vegetables with risk of colorectal cancerResearch in context

Author: Nikos Papadimitriou, Andre Kim, Eric S. Kawaguchi, John Morrison, Virginia Diez-Obrero, Demetrius Albanes, Sonja I. Berndt, Stéphane Bézieau, Stephanie A. Bien, D Timothy Bishop, Emmanouil Bouras, Hermann Brenner, Daniel D. Buchanan, Peter T. Campbell, Robert Carreras-Torres, Andrew T. Chan, Jenny Chang-Claude, David V. Conti, Matthew A. Devall, Niki Dimou, David A. Drew, Stephen B. Gruber, Tabitha A. Harrison, Michael Hoffmeister, Jeroen R. Huyghe, Amit D. Joshi, Temitope O. Keku, Anshul Kundaje, Sébastien Küry, Loic Le Marchand, Juan Pablo Lewinger, Li Li, Brigid M. Lynch, Victor Moreno, Christina C. Newton, Mireia Obón-Santacana, Jennifer Ose, Andrew J. Pellatt, Anita R. Peoples, Elizabeth A. Platz, Conghui Qu, Gad Rennert, Edward Ruiz-Narvaez, Anna Shcherbina, Mariana C. Stern, Yu-Ru Su, Duncan C. Thomas, Claire E. Thomas, Yu Tian, Konstantinos K. Tsilidis, Cornelia M. Ulrich, Caroline Y. Um, Kala Visvanathan, Jun Wang, Emily White, Michael O. Woods, Stephanie L. Schmit, Finlay Macrae, John D. Potter, John L. Hopper, Ulrike Peters, Neil Murphy, Li Hsu, Marc J. Gunter, and W. James Gauderman
Subjects: Diet, Fibre, Gene-environment interaction, Colorectal cancer, GWAS, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. Methods: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. Findings: The 3-DF joint test revealed two significant loci with p-value
Published: 2024
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6. Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations

Author: Minta Thomas, Yu-Ru Su, Elisabeth A. Rosenthal, Lori C. Sakoda, Stephanie L. Schmit, Maria N. Timofeeva, Zhishan Chen, Ceres Fernandez-Rozadilla, Philip J. Law, Neil Murphy, Robert Carreras-Torres, Virginia Diez-Obrero, Franzel J. B. van Duijnhoven, Shangqing Jiang, Aesun Shin, Alicja Wolk, Amanda I. Phipps, Andrea Burnett-Hartman, Andrea Gsur, Andrew T. Chan, Ann G. Zauber, Anna H. Wu, Annika Lindblom, Caroline Y. Um, Catherine M. Tangen, Chris Gignoux, Christina Newton, Christopher A. Haiman, Conghui Qu, D. Timothy Bishop, Daniel D. Buchanan, David R. Crosslin, David V. Conti, Dong-Hyun Kim, Elizabeth Hauser, Emily White, Erin Siegel, Fredrick R. Schumacher, Gad Rennert, Graham G. Giles, Heather Hampel, Hermann Brenner, Isao Oze, Jae Hwan Oh, Jeffrey K. Lee, Jennifer L. Schneider, Jenny Chang-Claude, Jeongseon Kim, Jeroen R. Huyghe, Jiayin Zheng, Jochen Hampe, Joel Greenson, John L. Hopper, Julie R. Palmer, Kala Visvanathan, Keitaro Matsuo, Koichi Matsuda, Keum Ji Jung, Li Li, Loic Le Marchand, Ludmila Vodickova, Luis Bujanda, Marc J. Gunter, Marco Matejcic, Mark A. Jenkins, Martha L. Slattery, Mauro D’Amato, Meilin Wang, Michael Hoffmeister, Michael O. Woods, Michelle Kim, Mingyang Song, Motoki Iwasaki, Mulong Du, Natalia Udaltsova, Norie Sawada, Pavel Vodicka, Peter T. Campbell, Polly A. Newcomb, Qiuyin Cai, Rachel Pearlman, Rish K. Pai, Robert E. Schoen, Robert S. Steinfelder, Robert W. Haile, Rosita Vandenputtelaar, Ross L. Prentice, Sébastien Küry, Sergi Castellví-Bel, Shoichiro Tsugane, Sonja I. Berndt, Soo Chin Lee, Stefanie Brezina, Stephanie J. Weinstein, Stephen J. Chanock, Sun Ha Jee, Sun-Seog Kweon, Susan Vadaparampil, Tabitha A. Harrison, Taiki Yamaji, Temitope O. Keku, Veronika Vymetalkova, Volker Arndt, Wei-Hua Jia, Xiao-Ou Shu, Yi Lin, Yoon-Ok Ahn, Zsofia K. Stadler, Bethany Van Guelpen, Cornelia M. Ulrich, Elizabeth A. Platz, John D. Potter, Christopher I. Li, Reinier Meester, Victor Moreno, Jane C. Figueiredo, Graham Casey, Iris Lansdorp Vogelaar, Malcolm G. Dunlop, Stephen B. Gruber, Richard B. Hayes, Paul D. P. Pharoah, Richard S. Houlston, Gail P. Jarvik, Ian P. Tomlinson, Wei Zheng, Douglas A. Corley, Ulrike Peters, and Li Hsu
Subjects: Science
Abstract: Abstract Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values
Published: 2023
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7. Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study

Author: Nikos Papadimitriou, Caroline J. Bull, Mazda Jenab, David J. Hughes, Joshua A. Bell, Eleanor Sanderson, Nicholas J. Timpson, George Davey Smith, Demetrius Albanes, Peter T. Campbell, Sébastien Küry, Loic Le Marchand, Cornelia M. Ulrich, Kala Visvanathan, Jane C. Figueiredo, Polly A. Newcomb, Rish K. Pai, Ulrike Peters, Kostas K. Tsilidis, Jolanda M. A. Boer, Emma E. Vincent, Daniela Mariosa, Marc J. Gunter, Tom G. Richardson, and Neil Murphy
Subjects: Obesity, Colorectal cancer, Mendelian randomization, Adult, Early life, Medicine
Abstract: Abstract Background Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk. Methods We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants. Results Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98–1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00–1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04–1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77–1.22) and colon cancer (OR: 0.97, 95% CI: 0.76–1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90–1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05). Conclusions Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.
Published: 2023
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8. SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice

Author: Salima El Chehadeh, Kyung Ah Han, Dongwook Kim, Gyubin Jang, Somayeh Bakhtiari, Dongseok Lim, Hee Young Kim, Jinhu Kim, Hyeonho Kim, Julia Wynn, Wendy K. Chung, Giuseppina Vitiello, Ioana Cutcutache, Matthew Page, Jozef Gecz, Kelly Harper, Ah-reum Han, Ho Min Kim, Marja Wessels, Allan Bayat, Alberto Fernández Jaén, Angelo Selicorni, Silvia Maitz, Arjan P. M. de Brouwer, Anneke Vulto-van Silfhout, Martin Armstrong, Joseph Symonds, Sébastien Küry, Bertrand Isidor, Benjamin Cogné, Mathilde Nizon, Claire Feger, Jean Muller, Erin Torti, Dorothy K. Grange, Marjolaine Willems, Michael C. Kruer, Jaewon Ko, Amélie Piton, and Ji Won Um
Subjects: Science
Abstract: The protein SLITRK2 plays an important role in synaptic communication. This study identifies X-linked SLITRK2 variants that underlie neurodevelopmental disorders by impairing excitatory synapses.
Published: 2022
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9. Missense variant contribution to USP9X-female syndrome

Author: Lachlan A. Jolly, Euan Parnell, Alison E. Gardner, Mark A. Corbett, Luis A. Pérez-Jurado, Marie Shaw, Gaetan Lesca, Catherine Keegan, Michael C. Schneider, Emily Griffin, Felicitas Maier, Courtney Kiss, Andrea Guerin, Kathleen Crosby, Kenneth Rosenbaum, Pranoot Tanpaiboon, Sandra Whalen, Boris Keren, Julie McCarrier, Donald Basel, Simon Sadedin, Susan M. White, Martin B. Delatycki, Tjitske Kleefstra, Sébastien Küry, Alfredo Brusco, Elena Sukarova-Angelovska, Slavica Trajkova, Sehoun Yoon, Stephen A. Wood, Michael Piper, Peter Penzes, and Jozef Gecz
Subjects: Medicine, Genetics, QH426-470
Abstract: Abstract USP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X-female syndrome also. We scrutinise the pathogenicity of eleven such variants, ten of which were novel. Combined application of variant prediction algorithms, protein structure modelling, and assessment under clinically relevant guidelines universally support their pathogenicity. The core phenotype of this cohort overlapped with previous descriptions of USP9X-female syndrome, but exposed heightened variability. Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X-female syndrome, and highlights major differences when compared to USP9X-male associated neurodevelopmental disorders.
Published: 2020
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10. Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

Author: Frédéric Ebstein, Sébastien Küry, Jonas Johannes Papendorf, and Elke Krüger
Subjects: ubiquitin, proteasome, autoinflammation, neurodevelopmental disorders, protein aggregation, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Over thirty years have passed since the first description of ubiquitin-positive structures in the brain of patients suffering from Alzheimer’s disease. Meanwhile, the intracellular accumulation of ubiquitin-modified insoluble protein aggregates has become an indisputable hallmark of neurodegeneration. However, the role of ubiquitin and a fortiori the ubiquitin-proteasome system (UPS) in the pathogenesis of neurodevelopmental disorders (NDD) is much less described. In this article, we review all reported monogenic forms of NDD caused by lesions in genes coding for any component of the UPS including ubiquitin-activating (E1), -conjugating (E2) enzymes, ubiquitin ligases (E3), ubiquitin hydrolases, and ubiquitin-like modifiers as well as proteasome subunits. Strikingly, our analysis revealed that a vast majority of these proteins have a described function in the negative regulation of the innate immune response. In this work, we hypothesize a possible involvement of autoinflammation in NDD pathogenesis. Herein, we discuss the parallels between immune dysregulation and neurodevelopment with the aim at improving our understanding the biology of NDD and providing knowledge required for the design of novel therapeutic strategies.
Published: 2021
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11. Enabling Global Clinical Collaborations on Identifiable Patient Data: The Minerva Initiative

Author: Christoffer Nellåker, Fowzan S. Alkuraya, Gareth Baynam, Raphael A. Bernier, Francois P.J. Bernier, Vanessa Boulanger, Michael Brudno, Han G. Brunner, Jill Clayton-Smith, Benjamin Cogné, Hugh J.S. Dawkins, Bert B.A. deVries, Sofia Douzgou, Tracy Dudding-Byth, Evan E. Eichler, Michael Ferlaino, Karen Fieggen, Helen V. Firth, David R. FitzPatrick, Dylan Gration, Tudor Groza, Melissa Haendel, Nina Hallowell, Ada Hamosh, Jayne Hehir-Kwa, Marc-Phillip Hitz, Mark Hughes, Usha Kini, Tjitske Kleefstra, R Frank Kooy, Peter Krawitz, Sébastien Küry, Melissa Lees, Gholson J. Lyon, Stanislas Lyonnet, Julien L. Marcadier, Stephen Meyn, Veronika Moslerová, Juan M. Politei, Cathryn C. Poulton, F Lucy Raymond, Margot R.F. Reijnders, Peter N. Robinson, Corrado Romano, Catherine M. Rose, David C.G. Sainsbury, Lyn Schofield, Vernon R. Sutton, Marek Turnovec, Anke Van Dijck, Hilde Van Esch, Andrew O.M. Wilkie, and The Minerva Consortium
Subjects: data sharing, phenotyping, patient information, data protection, rare disease, Faces, Genetics, QH426-470
Abstract: The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies. This includes the application of cutting-edge machine learning methods to image data. As with most digital tools employed in health care, there are ethical and data governance challenges associated with using identifiable personal image data. There are also risks with failing to deliver on the patient benefits of these new technologies, the biggest of which is posed by data siloing. The Minerva Initiative has been designed to enable the public good of deep phenotyping while mitigating these ethical risks. Its open structure, enabling collaboration and data sharing between individuals, clinicians, researchers and private enterprise, is key for delivering precision public health.
Published: 2019
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12. Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer.

Author: Jian Gong, Carolyn M Hutter, Polly A Newcomb, Cornelia M Ulrich, Stephanie A Bien, Peter T Campbell, John A Baron, Sonja I Berndt, Stephane Bezieau, Hermann Brenner, Graham Casey, Andrew T Chan, Jenny Chang-Claude, Mengmeng Du, David Duggan, Jane C Figueiredo, Steven Gallinger, Edward L Giovannucci, Robert W Haile, Tabitha A Harrison, Richard B Hayes, Michael Hoffmeister, John L Hopper, Thomas J Hudson, Jihyoun Jeon, Mark A Jenkins, Jonathan Kocarnik, Sébastien Küry, Loic Le Marchand, Yi Lin, Noralane M Lindor, Reiko Nishihara, Shuji Ogino, John D Potter, Anja Rudolph, Robert E Schoen, Petra Schrotz-King, Daniela Seminara, Martha L Slattery, Stephen N Thibodeau, Mark Thornquist, Reka Toth, Robert Wallace, Emily White, Shuo Jiao, Mathieu Lemire, Li Hsu, Ulrike Peters, and CCFR and GECCO
Subjects: Genetics, QH426-470
Abstract: Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10-8; permuted p-value 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74-0.91]; P = 2.1×10-4) and TT genotypes (OR,0.62 [95% CI, 0.51-0.75]; P = 1.3×10-6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk.
Published: 2016
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13. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

Author: Mengmeng Du, Shuo Jiao, Stephanie A Bien, Manish Gala, Goncalo Abecasis, Stephane Bezieau, Hermann Brenner, Katja Butterbach, Bette J Caan, Christopher S Carlson, Graham Casey, Jenny Chang-Claude, David V Conti, Keith R Curtis, David Duggan, Steven Gallinger, Robert W Haile, Tabitha A Harrison, Richard B Hayes, Michael Hoffmeister, John L Hopper, Thomas J Hudson, Mark A Jenkins, Sébastien Küry, Loic Le Marchand, Suzanne M Leal, Polly A Newcomb, Deborah A Nickerson, John D Potter, Robert E Schoen, Fredrick R Schumacher, Daniela Seminara, Martha L Slattery, Li Hsu, Andrew T Chan, Emily White, Sonja I Berndt, and Ulrike Peters
Subjects: Medicine, Science
Abstract: Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).
Published: 2016
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14. Genome-wide search for gene-gene interactions in colorectal cancer.

Author: Shuo Jiao, Li Hsu, Sonja Berndt, Stéphane Bézieau, Hermann Brenner, Daniel Buchanan, Bette J Caan, Peter T Campbell, Christopher S Carlson, Graham Casey, Andrew T Chan, Jenny Chang-Claude, Stephen Chanock, David V Conti, Keith R Curtis, David Duggan, Steven Gallinger, Stephen B Gruber, Tabitha A Harrison, Richard B Hayes, Brian E Henderson, Michael Hoffmeister, John L Hopper, Thomas J Hudson, Carolyn M Hutter, Rebecca D Jackson, Mark A Jenkins, Elizabeth D Kantor, Laurence N Kolonel, Sébastien Küry, Loic Le Marchand, Mathieu Lemire, Polly A Newcomb, John D Potter, Conghui Qu, Stephanie A Rosse, Robert E Schoen, Fred R Schumacher, Daniela Seminara, Martha L Slattery, Cornelia M Ulrich, Brent W Zanke, and Ulrike Peters
Subjects: Medicine, Science
Abstract: Genome-wide association studies (GWAS) have successfully identified a number of single-nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG) is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI). With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p
Published: 2012
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15. Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Author: Sébastien Küry, Jinwei Zhang, Thomas Besnard, Alfonso Caro-Llopis, Xue Zeng, Stephanie M. Robert, Sunday S. Josiah, Emre Kiziltug, Anne-Sophie Denommé-Pichon, Benjamin Cogné, Adam J. Kundishora, Le T. Hao, Hong Li, Roger E. Stevenson, Raymond J. Louie, Wallid Deb, Erin Torti, Virginie Vignard, Kirsty McWalter, F. Lucy Raymond, Farrah Rajabi, Emmanuelle Ranza, Detelina Grozeva, Stephanie A. Coury, Xavier Blanc, Elise Brischoux-Boucher, Boris Keren, Katrin Õunap, Karit Reinson, Pilvi Ilves, Ingrid M. Wentzensen, Eileen E. Barr, Solveig Heide Guihard, Perrine Charles, Eleanor G. Seaby, Kristin G. Monaghan, Marlène Rio, Yolande van Bever, Marjon van Slegtenhorst, Wendy K. Chung, Ashley Wilson, Delphine Quinquis, Flora Bréhéret, Kyle Retterer, Pierre Lindenbaum, Emmanuel Scalais, Lindsay Rhodes, Katrien Stouffs, Elaine M. Pereira, Sara M. Berger, Sarah S. Milla, Ankita B. Jaykumar, Melanie H. Cobb, Shreyas Panchagnula, Phan Q. Duy, Marie Vincent, Sandra Mercier, Brigitte Gilbert-Dussardier, Xavier Le Guillou, Séverine Audebert-Bellanger, Sylvie Odent, Sébastien Schmitt, Pierre Boisseau, Dominique Bonneau, Annick Toutain, Estelle Colin, Laurent Pasquier, Richard Redon, Arjan Bouman, Jill. A. Rosenfeld, Michael J. Friez, Helena Pérez-Peña, Syed Raza Akhtar Rizvi, Shozeb Haider, Stylianos E. Antonarakis, Charles E. Schwartz, Francisco Martínez, Stéphane Bézieau, Kristopher T. Kahle, Bertrand Isidor, Clinical Genetics, Clinical sciences, Medical Genetics, Reproduction and Genetics, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), University of Exeter, 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), The Greenwood Genetic Center, GeneDx [Gaithersburg, MD, USA], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Genève = University of Geneva (UNIGE), Yale School of Medicine [New Haven, Connecticut] (YSM), This work was granted by the French network of University Hospitals HUGO ('Hôpitaux Universitaires du Grand Ouest'), the French Ministry of Health, and and the Health Regional Agencies from Poitou-Charentes (represented by Frédérique Allaire), Bretagne, Pays de la Loire, and Centre-Val de Loire (HUGODIMS, 2013, RC14_0107). W.K.C. was supported by grants from Simons Foundation Autism Research Initiative, United
Subjects: MESH: Symporters, Exome sequencing, Male, KCC2, Mutation, Missense, MESH: Catalytic Domain, Neurodevelopmental disease, Protein Serine-Threonine Kinases, X-linked intellectual disability, MESH: Brain, WNK3, SDG 3 - Good Health and Well-being, Loss of Function Mutation, Catalytic Domain, MESH: Mental Retardation, X-Linked, Humans, Phosphorylation, MESH: Hemizygote, Genetics (clinical), Hemizygote, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Phosphorylation, Symporters, Brain, MESH: Loss of Function Mutation, MESH: Protein Serine-Threonine Kinases, MESH: Male, Mental Retardation, X-Linked, Maternal Inheritance, MESH: Maternal Inheritance
Abstract: PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had identifier with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. CONCLUSION: Pathogenic WNK3 variants cause a rare form of human X-linked identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.
Published: 2022
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16. Data from Genetic Predictors of Circulating 25-Hydroxyvitamin D and Risk of Colorectal Cancer

Author: Andrew T. Chan, Ulrike Peters, Peter Kraft, Brent W. Zanke, Kana Wu, Emily White, Jean Wactawski-Wende, Martha L. Slattery, Daniela Seminara, Fredrick R. Schumacher, Robert E. Schoen, John D. Potter, Kimmie Ng, Polly A. Newcomb, Hongmei Nan, JoAnn E. Manson, Jing Ma, Mathieu Lemire, Loic Le Marchand, Sébastien Küry, Mark A. Jenkins, Thomas J. Hudson, John L. Hopper, Michael Hoffmeister, Brian Henderson, Aditi Hazra, Richard B. Hayes, Tabitha A. Harrison, Edward L. Giovannucci, Steven Gallinger, Charles S. Fuchs, David Duggan, David V. Conti, Stephen J. Chanock, Jenny Chang-Claude, Graham Casey, Bette J. Caan, Hermann Brenner, Stéphane Bézieau, Sonja I. Berndt, John A. Baron, Carolyn M. Hutter, Conghui Qu, and Linda T. Hiraki
Abstract: Background: Experimental evidence has demonstrated an antineoplastic role for vitamin D in the colon, and higher circulating 25-hydroxyvitamin D [25(OH)D] levels are consistently associated with a lower risk of colorectal cancer. Genome-wide association studies have identified loci associated with levels of circulating 25(OH)D. The identified single-nucleotide polymorphisms (SNPs) from four gene regions collectively explain approximately 5% of the variance in circulating 25(OH)D.Methods: We investigated whether five polymorphisms in GC, CYP2R1, CYP24A1, and DHCR7/NADSYN1, genes previously shown to be associated with circulating 25(OH)D levels, were associated with colorectal cancer risk in 10,061 cases and 12,768 controls drawn from 13 studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR). We conducted a meta-analysis of crude and multivariate-adjusted logistic regression models to calculate odds ratios and associated confidence intervals for SNPs individually, SNPs simultaneously, and for a vitamin D additive genetic risk score (GRS).Results: We did not observe a statistically significant association between the 25(OH)D-associated SNPs and colorectal cancer marginally, conditionally, or as a GRS, or for colon or rectal cancer separately.Conclusions: Our findings do not support an association between SNPs associated with circulating 25(OH)D and risk of colorectal cancer. Additional work is warranted to investigate the complex relationship between 25(OH)D and colorectal cancer risk.Impact: There was no association observed between genetic markers of circulating 25(OH)D and colorectal cancer. These genetic markers account for a small proportion of the variance in 25(OH)D. Cancer Epidemiol Biomarkers Prev; 22(11); 2037–46. ©2013 AACR.
Published: 2023
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17. Supplementary Table 4 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author: Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter
Abstract: PDF file - 77K, All GxE interaction results.
Published: 2023
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18. Supplementary Table 2 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author: Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter
Abstract: PDF file - 55K, Study specific definitions of regular aspirin/NSAID use.
Published: 2023
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19. Supplementary Table 7 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author: Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter
Abstract: PDF file - 96K, All GxE interactions stratified by cancer site.
Published: 2023
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20. Supplementary Figure 1 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author: Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter
Abstract: PDF file - 52K, Forest plots for meta-analysis results with GxE interaction p < 0.01
Published: 2023
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21. Supplementary Table 3 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author: Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter
Abstract: PDF file - 67K, Descriptives for smoking, BMI, height, dietary variables, alcohol, sex, and NSAID use.
Published: 2023
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22. Supplementary Table 6 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author: Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter
Abstract: PDF file - 55K, Further information about main finding
Published: 2023
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23. Supplementary Table 1 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author: Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter
Abstract: PDF file - 168K, SNP details by study.
Published: 2023
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24. Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder

Author: Sébastien Küry, Frédéric Ebstein, Alice Mollé, Thomas Besnard, Ming-Kang Lee, Virginie Vignard, Tiphaine Hery, Mathilde Nizon, Grazia M.S. Mancini, Jacques C. Giltay, Benjamin Cogné, Kirsty McWalter, Wallid Deb, Hagar Mor-Shaked, Hong Li, Rhonda E. Schnur, Ingrid M. Wentzensen, Anne-Sophie Denommé-Pichon, Cynthia Fourgeux, Frans W. Verheijen, Eva Faurie, Rachel Schot, Cathy A. Stevens, Daphne J. Smits, Eileen Barr, Ruth Sheffer, Jonathan A. Bernstein, Chandler L. Stimach, Eliana Kovitch, Vandana Shashi, Kelly Schoch, Whitney Smith, Richard H. van Jaarsveld, Anna C.E. Hurst, Kirstin Smith, Evan H. Baugh, Suzanne G. Bohm, Emílie Vyhnálková, Lukáš Ryba, Capucine Delnatte, Juanita Neira, Dominique Bonneau, Annick Toutain, Jill A. Rosenfeld, Séverine Audebert-Bellanger, Brigitte Gilbert-Dussardier, Sylvie Odent, Frédéric Laumonnier, Seth I. Berger, Ann C.M. Smith, Franck Bourdeaut, Marc-Henri Stern, Richard Redon, Elke Krüger, Raphaël Margueron, Stéphane Bézieau, Jeremie Poschmann, Bertrand Isidor, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Universität Greifswald - University of Greifswald, Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University Medical Center [Utrecht], GeneDx [Gaithersburg, MD, USA], Hadassah Hebrew University Medical Center [Jerusalem], Emory University School of Medicine, Emory University [Atlanta, GA], Laboratoire de Biologie Neurovasculaire Intégrée [Angers] (CNRS UMR6214 - INSERM U771), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers, 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), University of Tennessee System, Stanford University, Duke University Medical Center, University of Alabama at Birmingham [ Birmingham] (UAB), Columbia University [New York], Charles University [Prague] (CU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Baylor College of Medicine (BCM), Baylor University, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Unité neurovasculaire et troubles cognitifs (Neuvacod), Université de Poitiers, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de référence Maladies Rares CLAD-Ouest [Rennes], Children's National Medical Center, National Human Genome Research Institute (NHGRI), Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Greifswald University Hospital, Research reported in this manuscript was supported by the NIH Common Fund through the Office of Strategic Coordination/Office of the NIH Director under award number U01HG007672 to V.S. Further support was obtained by funding from the German Research Foundation (SFBTR 167 A4, GRK2719 B4) to E.K, and Clinical Genetics
Subjects: Male, Heterozygote, Proteasome Endopeptidase Complex, tumor, Adolescent, T-Lymphocytes, Ubiquitin-Protein Ligases, [SDV]Life Sciences [q-bio], Mutation, Missense, UPS, ubiquitin-proteasome system, chromatin remodeling, Histones, SDG 3 - Good Health and Well-being, Loss of Function Mutation, Report, ubiquitin, Genetics, Humans, cancer, Family, BAP1, Child, deubiquitination, Germ-Line Mutation, Genetics (clinical), [SDV.GEN]Life Sciences [q-bio]/Genetics, neurodevelopment, BRCA1 Protein, Tumor Suppressor Proteins, Ubiquitination, Infant, Chromatin Assembly and Disassembly, BRCA1, Chromatin, Gene Expression Regulation, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, histone 2A, Female, Host Cell Factor C1, Ubiquitin Thiolesterase
Abstract: International audience; Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.
Published: 2022
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25. Stankiewicz-Isidor syndrome

Author: Ignacio Briceño, Frédéric Ebstein, Alberto Gómez, Heidi Cope, Wallid Deb, Krzysztof Szczaluba, Hutton M. Kearney, Dominique Bonneau, Elke Krüger, Marie Vincent, Jill A. Rosenfeld, Karin E. M. Diderich, Dominique Bourgeois, Kay Metcalfe, Bryce A. Mendelssohn, Magalie Barth, Solène Conrad, Alanna Strong, Patrick R. Blackburn, Amanda Gerard, McKinsey L. Goodenberger, Benjamin Cogné, Geneviève Baujat, Caroline Camby, Thomas Besnard, Natasha L. Rudy, Karin Dahan, Estelle Colin, Carlos A. Bacino, Caleb Bupp, Christel Thauvin-Robinet, Yolande van Bever, Rafał Płoski, Anne de Saint Martin, Johannes A. Mayr, Ingrid Bader, Yong-Hui Jiang, Virginie Vignard, Kathryn Warren, Judith D. Ranells, Yves Alembik, Joanna Kennedy, Stéphane Bézieau, Bertrand Isidor, Anna C.E. Hurst, Amélie Piton, Sébastien Küry, Ange-Line Bruel, PaweƗ Stankiewicz, Ingrid Scurr, Anja Brehm, and Clinical Genetics
Subjects: Genetics, Phenotype, Intellectual Disability, Molecular phenotype, Humans, Language Development Disorders, Haploinsufficiency, Biology, Genetics (clinical), Musculoskeletal Abnormalities
Abstract: Purpose: Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS. Methods: We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status. Results: The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes. Conclusion: We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.
Published: 2022
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26. Combining Asian-European Genome-Wide Association Studies of Colorectal Cancer Improves Risk Prediction Across Race and Ethnicity

Author: Minta Thomas, Yu-Ru Su, Elisabeth A. Rosenthal, Lori C Sakoda, Stephanie L Schmit, Maria N Timofeeva, Zhishan Chen, Ceres Fernandez-Rozadilla, Philip J Law, Neil Murphy, Robert Carreras-Torres, Virginia Diez-Obrero, Franzel JB van Duijnhoven, Shangqing Jiang, Aesun Shin, Alicja Wolk, Amanda I Phipps, Andrea Burnett-Hartman, Andrea Gsur, Andrew T Chan, Ann G Zauber, Anna H Wu, Annika Lindblom, Caroline Y Um, Catherine M Tangen, Chris Gignoux, Christina Newton, Christopher A. Haiman, Conghui Qu, D Timothy Bishop, Daniel D Buchanan, David R. Crosslin, David V Conti, Dong-Hyun Kim, Elizabeth Hauser, Emily White, Erin Siegel, Fredrick R Schumacher, Gad Rennert, Graham G Giles, Heather Hampel, Hermann Brenner, Isao Oze, Jae Hwan Oh, Jeffrey K Lee, Jennifer L Schneider, Jenny Chang-Claude, Jeongseon Kim, Jeroen R Huyghe, Jiayin Zheng, Jochen Hampe, Joel Greenson, John L Hopper, Julie R Palmer, Kala Visvanathan, Keitaro Matsuo, Koichi Matsuda, Keum Ji Jung, Li Li, Loic Le Marchand, Ludmila Vodickova, Luis Bujanda, Marc J Gunter, Marco Matejcic, Mark A Jenkins, Martha L Slattery, Mauro D’Amato, Meilin Wang, Michael Hoffmeister, Michael O Woods, Michelle Kim, Mingyang Song, Motoki Iwasaki, Mulong Du, Natalia Udaltsova, Norie Sawada, Pavel Vodicka, Peter T Campbell, Polly A Newcomb, Qiuyin Cai, Rachel Pearlman, Rish K Pai, Robert E Schoen, Robert S Steinfelder, Robert W Haile, Rosita Vandenputtelaar, Ross L Prentice, Sébastien Küry, Sergi Castellví-Bel, Shoichiro Tsugane, Sonja I Berndt, Soo Chin Lee, Stefanie Brezina, Stephanie J Weinstein, Stephen J Chanock, Sun Ha Jee, Sun-Seog Kweon, Susan Vadaparampil, Tabitha A Harrison, Taiki Yamaji, Temitope O Keku, Veronika Vymetalkova, Volker Arndt, Wei-Hua Jia, Xiao-Ou Shu, Yi Lin, Yoon-Ok Ahn, Zsofia K Stadler, Bethany Van Guelpen, Cornelia M Ulrich, Elizabeth A Platz, John D Potter, Christopher I Li, Reinier Meester, Victor Moreno, Jane C Figueiredo, Graham Casey, Iris Landorp Vogelaar, Malcolm G Dunlop, Stephen B Gruber, Richard B Hayes, Paul D P Pharoah, Richard S Houlston, Gail P Jarvik, Ian P Tomlinson, Wei Zheng, Douglas A Corley, Ulrike Peters, and Li Hsu
Subjects: Article
Abstract: Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expanded PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS were 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1,681-3,651 cases and 8,696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They were significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values
Published: 2023

27. Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families

Author: Monica H. Wojcik, Siddharth Srivastava, Pankaj B. Agrawal, Tugce B. Balci, Bert Callewaert, Pier Luigi Calvo, Diana Carli, Michelle Caudle, Samantha Colaiacovo, Laura Cross, Kalliope Demetriou, Katy Drazba, Marina Dutra‐Clarke, Matthew Edwards, Casie A. Genetti, Dorothy K. Grange, Scott E. Hickey, Bertrand Isidor, Sébastien Küry, Herbert M. Lachman, Alinoe Lavillaureix, Michael J. Lyons, Carlo Marcelis, Elysa J. Marco, Julian A. Martinez‐Agosto, Catherine Nowak, Antonio Pizzol, Marc Planes, Eloise J. Prijoles, Evelise Riberi, Eric T. Rush, Bianca E. Russell, Rani Sachdev, Betsy Schmalz, Deborah Shears, David A. Stevenson, Kate Wilson, Sandra Jansen, Bert B. A. de Vries, and Cynthia J. Curry
Subjects: All institutes and research themes of the Radboud University Medical Center, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetics, Genetics (clinical)
Abstract: Item does not contain fulltext Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation. 01 juli 2023
Published: 2023

28. Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study

Author: Nikos Papadimitriou, Caroline J Bull, Mazda Jenab, David J. Hughes, Joshua A Bell, Eleanor Sanderson, Nicholas J Timpson, George Davey Smith, Demetrius Albanes, Peter T Campbell, Sébastien Küry, Loic Le Marchand, Cornelia M Ulrich, Kala Visvanathan, Jane C Figueiredo, Polly A Newcomb, Rish K Pai, Ulrike Peters, Kostas K Tsilidis, Jolanda M.A. Boer, Emma E Vincent, Daniela Mariosa, Marc J Gunter, Tom G Richardson, and Neil Murphy
Subjects: Adult, Pediatric Obesity, General Medicine, Middle Aged, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Body Mass Index, Adiposity/genetics, Risk Factors, Colonic Neoplasms, Humans, Child, Bristol Population Health Science Institute, Adiposity, Genome-Wide Association Study
Abstract: Background Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk. Methods We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants. Results Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98–1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00–1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04–1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77–1.22) and colon cancer (OR: 0.97, 95% CI: 0.76–1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90–1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05). Conclusions Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.
Published: 2022
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29. Abstract 5223: Circulating lipoprotein lipids and colorectal cancer risk: A Mendelian randomization analysis from the GECCO consortium

Author: Lili Liu, Wanqing Wen, Jirong Long, Themistocles L Assimes, Luis Bujanda, Stephen B Gruber, Sébastien Küry, Brigid Lynch, Conghui Qu, Minta Thomas, Emily White, Michael O. Woods, Ulrike Peters, and Wei Zheng
Subjects: Cancer Research, Oncology
Abstract: Background Conventional observational studies have reported conflicting results regarding the association between low density lipoprotein cholesterol (LDL-C) and risk of colorectal cancer (CRC). We conducted a Mendelian randomization analysis to address this association. Methods Single-nucleotide polymorphisms (SNPs) associated with five blood lipids (total cholesterol, HDL-C, high-density lipoprotein cholesterol [HDL-C], non-HDL-C, and triglyceride) were obtained from a genome-wide association study (GWAS) meta-analysis of European ancestry in the Global Lipids Genetics Consortium (GLGC, N ≤ 1 319 982), and two lipids (apolipoprotein A1 and apolipoprotein B) from a GWAS in the UK Biobank (UKB, N ≤ 441 016). Summary statistics were obtained for these SNPs from a GWAS of CRC in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) including 34,869 cases and 29,051 controls. Associations with CRC risk per one standard deviation increase in the genetically predicted lipids level were generated using inverse-variance weighted random-effects models. Results No overall association was observed between genetically predicted levels of blood lipids and CRC risk. However, increased risks were observed for all LDL-C related traits among women, including total cholesterol (OR = 1.10; 95%CI = 1.02, 1.18), LDL-C (1.07; 1.00, 1.14), non-HDL-C (1.09; 1.02, 1.16), and apolipoprotein B (1.11; 1.02, 1.21); whereas no significant association was found among men. Similar but ostensibly stronger associations of these traits were seen with distal colon cancer cases, with no significant association showing on proximal colon or rectum cancer cases. We also observed similar positive associations of LDL-C related traits among those having CRC before their 50 years. Of note, risk reduction was found for apolipoprotein A1, a major component of HDL-C, in these early-onset cases (0.87; 0.78, 0.98). Conclusion Results from this study suggest that high circulating LDL-C levels may increase the risk of CRC, particularly cancer of the distal colon, and the association may differ by sex and age at CRC onset. Key words: Blood lipids; colorectal cancer; Mendelian randomization. Citation Format: Lili Liu, Wanqing Wen, Jirong Long, Themistocles L Assimes, Luis Bujanda, Stephen B Gruber, Sébastien Küry, Brigid Lynch, Conghui Qu, Minta Thomas, Emily White, Michael O. Woods, Ulrike Peters, Wei Zheng. Circulating lipoprotein lipids and colorectal cancer risk: A Mendelian randomization analysis from the GECCO consortium. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5223.
Published: 2023
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30. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Author: Zaid Afawi, Shekeeb S. Mohammad, Geoffrey Wallace, Ayelet Zerem, Amy L Schneider, Kyra E. Stuurman, Deepak Gill, Alison M. Muir, Russell C. Dale, Gali Heimer, Martino Montomoli, Elena Gardella, Emmanuelle Ranza, Simone Mandelstam, Peter Procopis, Øyvind L. Busk, Christian Korff, Arjan Bouman, Boudewijn Gunning, Connie T.R.M. Stumpel, Yunus Balcik, Christa de Geus, Philipp S. Reif, Yue-Hua Zhang, Sameer M. Zuberi, Volodymyr Kharytonov, Sébastien Küry, Patrick Edery, Sebastien Moutton, Trine Bjørg Hammer, Hannah Stamberger, Joseph D. Symonds, Gaetan Lesca, Samuel F. Berkovic, Massimiliano Rossi, Danique R.M. Vlaskamp, Eric W. Klee, Mark T Mackay, Felix Rosenow, Erica L. Macke, Chirag Patel, Jacob Bie Granild-Jensen, Helenius J. Schelhaas, Danielle M. Andrade, Lynette G. Sadleir, Iris M de Lange, Roseline Caumes, Eva Morava, Frédéric Tran Mau-Them, Anita Cairns, Keren Yosovich, Jing Zhang, Bruria Ben Zeev, Nicolas Chatron, Dorit Lev, Laura Reed, Pauline Monin, Eva H. Brilstra, Birgitte Bertelsen, Georgie Hollingsworth, Nienke E. Verbeek, Heather C Mefford, Rikke S. Møller, Johan R. Helle, Christina Fenger, Meriel McEntagart, Thomas Smol, Mark F. Bennett, Yuri A. Zarate, Renzo Guerrini, Elena Parrini, Candace T. Myers, Judith S. Verhoeven, Bertrand Isidor, Ruth Shalev, David A. Koolen, Ingrid E. Scheffer, Bobby P. C. Koeleman, Lauren Gunderson, Michael S. Hildebrand, Tara Sadoway, Richard J. Leventer, Sanjay M. Sisodiya, Krati Shah, Edith P. Almanza Fuerte, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, and Clinical Genetics
Subjects: Male, Pediatrics, medicine.medical_specialty, INTELLECTUAL DISABILITY, Autism Spectrum Disorder, Encephalopathy, Nerve Tissue Proteins, ILAE COMMISSION, MOSAICISM, Epilepsy/genetics, CLASSIFICATION, Epilepsy, Brain Diseases/genetics, Genes, X-Linked, Seizures, Intellectual disability, Genotype, medicine, Humans, developmental and epileptic encephalopathy, MYOCLONIA, Atonic seizure, Genetics (clinical), Brain Diseases, ddc:618, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], KIAA2022, business.industry, MUTATIONS, medicine.disease, Phenotype, Autism Spectrum Disorder/genetics, Genes, X-Linked/genetics, Autism spectrum disorder, intellectual disability, NEXMIF, Autism, epilepsy, Female, INACTIVATION, Human medicine, Seizures/genetics, business, POSITION PAPER
Abstract: Contains fulltext : 231688.pdf (Publisher’s version ) (Closed access) PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
Published: 2021
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31. Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants inLARS1

Author: Nicola Dikow, Alyssa Bianzano, Robert Kopajtich, James R. Lupski, Gajja S. Salomons, Jennifer E. Posey, Saskia Biskup, Jill A. Rosenfeld, Bruce H. R. Wolffenbuttel, Dominic Lenz, Saskia B. Wortmann, Denise Horn, Urania Kotzaeridou, Joanne Hughes, Maya Huijberts, Simone Kathemann, Tobias B. Haack, Stefan Kölker, Elke Lainka, Ralf A. Husain, Fleur Vansenne, Sébastien Küry, Andrea Hanson-Kahn, Bertrand Isidor, Matias Wagner, Ellen Crushell, Inga Harting, Jonathan A. Bernstein, Lucia Laugwitz, Dominique Caldari, Desirée E.C. Smith, Marisa I. Mendes, Christian Staufner, Julian Schröter, Claire Reynolds, Heiko Brennenstuhl, Claudia Weiß, Bader Alhaddad, Holger Prokisch, Georg F. Hoffmann, Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Medicine, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Gastroenterology Endocrinology Metabolism, and Amsterdam Reproduction & Development (AR&D)
Subjects: medicine.medical_specialty, HOMEOSTASIS, Microcytic anemia, Medizin, Disease, Gastroenterology, DISEASE, MECHANISMS, TRANSFER-RNA SYNTHETASES, Seizures, Internal medicine, Genotype, medicine, Humans, Stroke, Genetics (clinical), RECESSIVE MUTATIONS, medicine.diagnostic_test, Muscular hypotonia, business.industry, infantile liver failure syndrome type 1, Magnetic resonance imaging, LARS1, acute liver failure, medicine.disease, Phenotype, aminoacyl-tRNA synthetase deficiency, Mutation, ONSET, Muscle Hypotonia, business, Lars1, Infantile Liver Failure Syndrome Type 1, Acute Liver Failure, Aminoacyl-trna Synthetase Deficiency, Metabolic Stroke, metabolic stroke, Liver Failure, Homeostasis
Abstract: Purpose: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. Methods: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. Results: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. Conclusion: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.
Published: 2020
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32. De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation

Author: Dongxue Mao, Chloe M. Reuter, Maura R.Z. Ruzhnikov, Anita E. Beck, Emily G. Farrow, Lisa T. Emrick, Jill A. Rosenfeld, Katherine M. Mackenzie, Laurie Robak, Matthew T. Wheeler, Lindsay C. Burrage, Mahim Jain, Pengfei Liu, Daniel Calame, Sébastien Küry, Martin Sillesen, Klaus Schmitz-Abe, Davide Tonduti, Luigina Spaccini, Maria Iascone, Casie A. Genetti, Mary K. Koenig, Madeline Graf, Alyssa Tran, Mercedes Alejandro, Brendan H. Lee, Isabelle Thiffault, Pankaj B. Agrawal, Jonathan A. Bernstein, Hugo J. Bellen, Hsiao-Tuan Chao, Maria T. Acosta, Margaret Adam, David R. Adams, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Raphael Bernier, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Lauren C. Briere, Elly Brokamp, Elizabeth A. Burke, Manish J. Butte, Peter Byers, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Yong-hui Jiang, Jean M. Johnston, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Kimberly LeBlanc, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Genecee Renteria, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Monte Westerfield, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner
Subjects: Male, 0301 basic medicine, Proband, Ataxia, Adolescent, Developmental Disabilities, Nervous System Malformations, Leukoencephalopathy, eIF-2 Kinase, 03 medical and health sciences, 0302 clinical medicine, Leukoencephalopathies, Report, Genetics, medicine, Humans, Missense mutation, Kinase activity, Child, Genetics (clinical), biology, Leukodystrophy, Genetic Variation, Infant, medicine.disease, White Matter, Hypotonia, Hereditary Central Nervous System Demyelinating Diseases, 030104 developmental biology, Child, Preschool, eIF2B, Immunology, biology.protein, Female, medicine.symptom, 030217 neurology & neurosurgery
Abstract: EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.
Published: 2020
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33. GestaltMatcher facilitates rare disease matching using facial phenotype descriptors

Author: Tzung-Chien Hsieh, Aviram Bar-Haim, Shahida Moosa, Nadja Ehmke, Karen W. Gripp, Jean Tori Pantel, Magdalena Danyel, Martin Atta Mensah, Denise Horn, Stanislav Rosnev, Nicole Fleischer, Guilherme Bonini, Alexander Hustinx, Alexander Schmid, Alexej Knaus, Behnam Javanmardi, Hannah Klinkhammer, Hellen Lesmann, Sugirthan Sivalingam, Tom Kamphans, Wolfgang Meiswinkel, Frédéric Ebstein, Elke Krüger, Sébastien Küry, Stéphane Bézieau, Axel Schmidt, Sophia Peters, Hartmut Engels, Elisabeth Mangold, Martina Kreiß, Kirsten Cremer, Claudia Perne, Regina C. Betz, Tim Bender, Kathrin Grundmann-Hauser, Tobias B. Haack, Matias Wagner, Theresa Brunet, Heidi Beate Bentzen, Luisa Averdunk, Kimberly Christine Coetzer, Gholson J. Lyon, Malte Spielmann, Christian P. Schaaf, Stefan Mundlos, Markus M. Nöthen, and Peter M. Krawitz
Subjects: Genetics
Abstract: Many monogenic disorders cause a characteristic facial morphology. Artificial intelligence can support physicians in recognizing these patterns by associating facial phenotypes with the underlying syndrome through training on thousands of patient photographs. However, this ‘supervised’ approach means that diagnoses are only possible if the disorder was part of the training set. To improve recognition of ultra-rare disorders, we developed GestaltMatcher, an encoder for portraits that is based on a deep convolutional neural network. Photographs of 17,560 patients with 1,115 rare disorders were used to define a Clinical Face Phenotype Space, in which distances between cases define syndromic similarity. Here we show that patients can be matched to others with the same molecular diagnosis even when the disorder was not included in the training set. Together with mutation data, GestaltMatcher could not only accelerate the clinical diagnosis of patients with ultra-rare disorders and facial dysmorphism but also enable the delineation of new phenotypes.
Published: 2022

34. De novo variants in thePSMC3proteasome AAA-ATPase subunit gene cause neurodevelopmental disorders associated with type I interferonopathies

Author: Tianyun Wang, Elke Krueger, Sébastien KÜRY, Frederic Laumonnier, and Thomas Besnard
Abstract: A critical step in preserving protein homeostasis by the ubiquitin-proteasome system (UPS) is the recognition, binding, unfolding, and translocation of protein substrates by AAA-ATPase proteasome subunits for degradation by 26S proteasomes. Here, we identified fourteen differentde novomissense variants in thePSMC3gene encoding the AAA-ATPase proteasome subunit Rpt5 in twenty-two unrelated heterozygous subjects with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Indeed, depletion ofPSMC3impaired reversal learning capabilities in aDrosophilamodel. ThePSMC3variants cause proteasome dysfunction in patient-derived cells by disruption of substrate translocation, proteotoxic stress and proteostatic imbalances, as well as alterations in proteins controlling developmental and innate immune programs. Molecular analysis confirmed the induction of cellular stress responses and dysregulated mitophagy along with an elevated type I interferon (IFN) signature. Our data definePSMC3variants as the genetic cause of proteotoxic stress alerting the innate immune system to mount a type I IFN response and link neurodevelopmental syndromes to interferonopathies.
Published: 2021
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35. Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies

Author: Francisca Millan, Mieke M. van Haelst, Ankita Patel, Cédric Le Caignec, Jean P. Pfotenhauer, Wendy E. Smith, Denise Horn, Klaske D. Lichtenbelt, Tanner Hagelstrom, David A. Dyment, Ryan J. Taft, Jill V. Hunter, Jolanta Wierzba, Margarita Saenz, Ian D. Krantz, Denise L. Perry, Luis F. Escobar, Bertrand Isidor, Ingrid Cristian, Richard E. Person, Aditi Chawla, Michael D. Fountain, Diane Masser-Frye, Sarah E. Raible, Koen L.I. van Gassen, Erin Torti, Weimin Bi, Philip J. Lupo, Jill A. Rosenfeld, Chumei Li, Claude Férec, Robert C. Pedersen, Megan E. Rech, Fan Xia, Sébastien Küry, Ilaria Parenti, Ingrid M. Wentzensen, Loren D M Pena, Jane Juusola, Manuel Holtgrewe, Frank J. Kaiser, John M. McCarthy, David S. Oleson, Arnold Munnich, Kévin Uguen, Thomas M. Morgan, Lara Segebrecht, Sung Hae L. Kang, Nadja Ehmke, Sunita Venkateswaran, Christian P. Schaaf, Marilyn C. Jones, Tim M. Strom, Rocio Moran, Stéphane Bézieau, Rebecca C. Spillmann, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: speech delay, Autism Spectrum Disorder, Autism, Haploinsufficiency, Bioinformatics, Whole Exome Sequencing, white matter paucity, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, 2.1 Biological and endogenous factors, Genetics(clinical), Child, Genetics (clinical), Exome sequencing, Pediatric, Genetics & Heredity, 0303 health sciences, Genome, neurodevelopment, Nuclear Proteins, Phenotype, Hypotonia, ddc, 3. Good health, DNA-Binding Proteins, Mental Health, Autism spectrum disorder, Speech delay, Chromosome Deletion, medicine.symptom, Human, Adolescent, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Article, 03 medical and health sciences, Clinical Research, Usp7, Neurodevelopment, Speech Delay, White Matter Paucity, Corpus Callosum Thinning, Intellectual Disability, 030225 pediatrics, Behavioral and Social Science, Genetics, medicine, Humans, Language Development Disorders, Preschool, 030304 developmental biology, Problem Behavior, business.industry, corpus callosum thinning, Neurosciences, Proteins, Infant, Newborn, medicine.disease, Brain Disorders, Neurodevelopmental Disorders, USP7, Congenital Structural Anomalies, business
Abstract: Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.
Published: 2019
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36. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

Author: Philippe M. Campeau, Katherine Agre, Vernon R. Sutton, Kirsty McWalter, Bertrand Isidor, Øystein L. Holla, Anna Lehman, Megha Desai, Jonathan Berg, Stéphane Bézieau, Rolph Pfundt, Jennifer Tarpinian, Jennifer B. Humberson, Holly A.F. Stessman, Madeleine R. Geisheker, Emma Bedoukian, Shalini N. Jhangiani, Marine I. Murphree, Annapurna Poduri, Anne-Sophie Denommé-Pichon, Christian Gilissen, Yaping Yang, Eliane Beauregard-Lacroix, Claude Férec, Francesca Filippini, Anne Guimier, Daryl A. Scott, Stephen Sanders, Julie C. Sapp, Ralitza H. Gavrilova, Slavé Petrovski, Ann Nordgren, Sylvia Redon, Ernie M.H.F. Bongers, Shelagh Joss, Jill A. Rosenfeld, Wallid Deb, Ingrid M. Wentzensen, Usha Kini, Vandana Shashi, Mindy H. Li, Stanislas Lyonnet, Thomas Garcia, Øyvind L. Busk, Christoffer Nellåker, Amber Begtrup, Brigitte Gilbert-Dussardier, Thomas Besnard, Francois V. Bolduc, Patrick R. Blackburn, Justine Rousseau, Frédéric Bilan, Eric W. Klee, Christopher T. Gordon, Pavel N. Pichurin, Peggy Kulch, Kevin P. Lally, Laurie Robak, Arnaud Picard, Kristian Tveten, Meredith Park, Sébastien Küry, Jaya Punetha, Moira Blyth, Asbjørg Stray-Pedersen, Jacqueline Harris, Erin L. Heinzen, Nicholas Stong, Cara M. Skraban, Julie S. Cohen, Aida Telegrafi, Xenia Latypova, Zeynep Coban Akdemir, Jacob Zyskind, Caitlin Troyer, Xiang-Jiao Yang, Tuula Rinne, Leslie G. Biesecker, Jennifer E. Posey, Kyle Retterer, Jeanne Amiel, Rui Xiao, Magnus Nordenskjöld, Tammie Dewan, Jennifer A. Sullivan, Charlotte von der Lippe, Evan E. Eichler, Anna Lindstrand, Dominique Bonneau, Yuri A. Zarate, Elaine H. Zackai, Fayth M. Kalb, Daniel H. Lowenstein, Shiri Avni, Benjamin Cogné, Jennifer J. Johnston, Kerri H. Whitlock, Catherine Shain, Séverine Audebert-Bellanger, Malin Kvarnung, Oana Caluseriu, David Goldstein, Annick Toutain, Andres Hernandez-Garcia, Brina Daniels, Sophie Ehresmann, James R. Lupski, Julie McGaughran, Ashley H Ebanks, Kévin Uguen, Marine Legendre, Sylvie Odent, Richard Redon, Erica H. Gerkes, Xiaofei Song, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Sainte Justine [Montréal], Université du Québec à Montréal = University of Québec in Montréal (UQAM), University of Oxford [Oxford], GeneDx [Gaithersburg, MD, USA], Mayo Clinic [Rochester], University of California [San Francisco] (UCSF), University of California, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement Français du Sang Bretagne, EFS, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Johns Hopkins University School of Medicine [Baltimore], Kennedy Krieger Institute [Baltimore], Chapel Allerton Hospital, University of British Columbia (UBC), University of Dundee, Rush University Medical Center [Chicago], Oxford University Hospitals NHS Trust, Queen Elizabeth University Hospital (Glasgow), Trondheim University, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Virginia [Charlottesville], Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, University of Pennsylvania [Philadelphia], National Human Genome Research Institute (NHGRI), Harvard Medical School [Boston] (HMS), Karolinska University Hospital [Stockholm], Duke University Medical Center, University of Groningen [Groningen], University of Arkansas for Medical Sciences (UAMS), McGovern Medical School [Houston, Texas], The University of Texas Health Science Center at Houston (UTHealth), Phoenix Children's Hospital, Columbia University [New York], University of Southern Queensland (USQ), Telemark Hospital Trust [Skien, Norway], University of Washington [Seattle], Oslo University Hospital [Oslo], Children’s Hospital of Philadelphia (CHOP ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Radboud University Medical Center [Nijmegen], Ann & Robert H. Lurie Children's Hospital of Chicago, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], 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), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Alberta, Boston Children's Hospital, McGill University Health Center [Montreal] (MUHC), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Creighton University Medical School [Omaha, NE, USA], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), National Institute of Neurological Disorders and Stroke, K08 HG008986, National Human Genome Research Institute, BC Children’s Hospital Foundation, Genome British Columbia, Fonds de Recherche du Québec - Santé, Canadian Institutes of Health Research, Center for Individualized Medicine, Mayo Clinic, Health Regional Agency from Poitou-Charentes, French Ministry of Health, RC14_0107, HUGODIMS, NS053998, The Epilepsy Phenome/Genome Project, NS077303, Epi4K, Duke Genome Sequencing Clinic, NINDS R35 NS105078, National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, HG200328 12, intramural research program of the NHGRI, Dart NeuroScience, Kids Brain Health Network, Mining for Miracles, UM1 HG006542, National Heart, Lung, and Blood Institute, CIM Investigative and Functional Genomics Program, R01MH101221, National Institute of Mental Health, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Virginia, University of Pennsylvania, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), CCSD, Accord Elsevier, Faculteit Medische Wetenschappen/UMCG, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: CHROMATIN, Male, 0301 basic medicine, Autism, Sequence Homology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Medical and Health Sciences, 0302 clinical medicine, SCHIZOPHRENIA, Gene expression, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, de novo variants, Genetics (clinical), Pediatric, Genetics & Heredity, Genetics, biology, neurodevelopmental disorders, histone acetylation, Adaptor Proteins, Nuclear Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Biological Sciences, Prognosis, Phenotype, Chromatin, Mental Health, Histone, intellectual disability, Child, Preschool, Female, REGULATOR, congenital malformations, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], BRAIN-DEVELOPMENT, Adult, Adolescent, Histone acetyltransferase complex, Intellectual and Developmental Disabilities (IDD), Mutation, Missense, Deciphering Developmental Disorders study, autism spectrum disorder, KAT6B, RNAI SCREEN, Young Adult, 03 medical and health sciences, CAUSES Study, Rare Diseases, Intellectual Disability, Report, COFACTOR, medicine, RUBINSTEIN-TAYBI-SYNDROME, Humans, Amino Acid Sequence, Autistic Disorder, Preschool, Gene, Genetic Association Studies, Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Rubinstein–Taybi syndrome, Signal Transducing, Neurosciences, Infant, medicine.disease, TRRAP, Brain Disorders, SELF-RENEWAL, 030104 developmental biology, DE-NOVO MUTATIONS, Mutation, biology.protein, Missense, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 202928.pdf (Publisher’s version ) (Open Access) Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
Published: 2019
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37. Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Author: Katja Butterbach, Julyann Pérez-Mayoral, Douglas F. Easton, Stefanie Brezina, Ben Zhang, Frank J. Manion, Hansong Wang, Sanford D. Markowitz, Liesel M. FitzGerald, Sun Ha Jee, Michelle Cotterchio, Daniel D. Buchanan, Timothy R. Church, Wolfgang Lieb, Xiao-Ou Shu, John L. Hopper, Stephanie A. Bien, Manuela Gago-Dominguez, Jian Gong, Laurence N. Kolonel, Graham G. Giles, Leon Raskin, Yingchang Lu, Kristen Anton, Charles S. Fuchs, Fränzel J.B. van Duijnhoven, Hermann Brenner, Yi Lin, Clicerio Gonzalez-Villalpando, Yong-Bing Xiang, Aaron K. Aragaki, Daniela Seminara, Stephanie M. Gogarten, Gad Rennert, Jose E. Castelao, Rocky Fischer, Antonio J. Molina, Jarmo Virtamo, Tabitha A. Harrison, Volker Arndt, Lee Soo Chin, Michael Hoffmeister, Mark A. Jenkins, Shu Chen Huang, Chris S. Carlson, Stéphane Bézieau, Rebecca D. Jackson, Bhramar Mukherjee, Darin Taverna, Bridget M. Riggs, Christopher K. Edlund, Christopher A. Haiman, Melissa C. Southey, Anna H. Wu, Marilena Melas, Antonia Trichopoulou, Hedy S. Rennert, Gianluca Severi, Stephen B. Gruber, Noralane M. Lindor, Gerhard A. Coetzee, Richard B. Hayes, Sarah J. Plummer, Keitaro Matsuo, Mathieu Lemire, Philipp Hofer, Neil Murphy, José María Huerta, Paul D.P. Pharoah, Erin M. Siegel, Sébastien Küry, Thomas J. Hudson, Annika Lindblom, Marcia Cruz Correa, Michael O. Woods, Sophia Harlid, Tilman Kuehn, David Shibata, Christopher I. Li, Stephen N. Thibodeau, Stephen J. Chanock, Jochen Hampe, Flavio Lejbkowicz, Jeroen R. Huyghe, Suminori Kono, Jenny Chang-Claude, Aung Ko Win, Brent W. Zanke, Alicja Wolk, David V. Conti, Elena M. Gonzalez-Villalpando, Christopher I. Amos, Shuo Jiao, Domenico Palli, Vicente Martín, Jesus P. Paredes Cotoré, Stephanie J. Weinstein, Andrea Gsur, William M. Grady, Koichi Matsuda, Loic Le Marchand, Hanane Omichessan, Marc J. Gunter, Graham Casey, Li Li, Zsofia K. Stadler, Eric J. Jacobs, Kevin McDonnell, Dallas R. English, Demetrius Albanes, Amit Joshi, Wei Zheng, Mariana C. Stern, Cecelia A. Laurie, Jing Ma, Cornelia M. Ulrich, Stephanie L. Schmit, Victor Moreno, John D. Potter, Chenxu Qu, Bette J. Caan, Heinz-Josef Lenz, M. Henar Alonso, Andrea Z. LaCroix, Christoph Mancao, John F. Harju, Yun Ru Liu, Jane C. Figueiredo, Gregory Idos, Kana Wu, Duncan C. Thomas, Motoki Iwasaki, W. James Gauderman, Thomas A. Sellers, David Van Den Berg, Barbara K. Fortini, David N. Levine, James M. Church, Ya Wen Cheng, Edith J. M. Feskens, Edward Giovannucci, Manish Gala, Polly A. Newcomb, Charles Kooperberg, Iona Cheng, David J. Hunter, Martha L. Slattery, Roger L. Milne, Lars G. Fritsche, Niha Zubair, Steven Gallinger, Yi Xin Zeng, Wei Shi, Andrew T. Chan, Fotios Loupakis, Vittorio Krogh, Clemens Schafmayer, Sun-Seog Kweon, Bethany van Guelpan, Amanda Bloomer, Kenneth Offit, Stephanie Tring, Shoichiro Tsugane, David Duggan, Fredrick R. Schumacher, Joseph Vijai, Weihua Jia, Marie-Christine Boutron-Ruault, Joel K. Greenson, Frank Luh, Ulrike Peters, Keith R. Curtis, Juergen Boehm, Robert E. Schoen, Sonja I. Berndt, Elizabeth L. Barry, Sebastian Stintzing, Li Hsu, Emily White, Conghui Qu, Peter T. Campbell, Caroline McNeil, and Yun Yen
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Genotype, Nutrition and Disease, Colorectal cancer, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Càncer colorectal, Internal medicine, Voeding en Ziekte, Ethnicity, medicine, Genetic predisposition, Genetics, Humans, Life Science, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Allele, Allele frequency, Genetic association, VLAG, Global Nutrition, Wereldvoeding, Oncology And Carcinogenesis, Case-control study, Articles, Prognosis, medicine.disease, United States, 3. Good health, Genetic Loci, Case-Control Studies, 030220 oncology & carcinogenesis, Colorectal Neoplasms, Genètica, Follow-Up Studies, Genome-Wide Association Study
Abstract: Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
Published: 2019
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38. Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

Author: Stéphane Bézieau, Médéric Jeanne, Anne Sophie Denommé-Pichon, Jason Laufman, William B. Dobyns, Sébastien Küry, Judith Halewa, Elliott H. Sherr, Dominique Bonneau, Julie Vogt, Sophie Blesson, Hélène Demory, Jérôme Honnorat, Helene Cox, Séverine Audebert-Bellanger, Marie Laure Vuillaume, Sylviane Marouillat, Estelle Colin, Avgi Andreou, Emanuela Argilli, Bertrand Isidor, Bernhard Lohkamp, Miroslava Hancarova, Rajesh Khanna, Davit Babikyan, Sarka Bendova, Kimberly A. Aldinger, Aubin Moutal, Saskia M. Maas, Marjon van Slegtenhorst, Annick Toutain, Sylvie Odent, Rose Anne Thépault, Natella Kostandyan, Eleina M. England, Zdenek Sedlacek, Richard Redon, M. Mahdi Motazacker, Frédéric Laumonnier, Brigitte Gilbert-Dussardier, Grazia M.S. Mancini, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University of Arizona, Amsterdam UMC - Amsterdam University Medical Center, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Birmingham Women's and Children's NHS Foundation Trust, University of Akron, Yerevan State Medical University after Mkhitar Heratsi, Charles University [Prague] (CU), Center for Integrative Brain Research, University of Washington [Seattle], University of California [Los Angeles] (UCLA), University of California (UC), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], 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), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Karolinska Institutet [Stockholm], National Human Genome Research Institute, Ministry of Health of the Czech Republic, DGOS, Wellcome Trust, Chard-Hutchinson, Xavier, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Amsterdam UMC, University of California, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Human Genetics, ANS - Cellular & Molecular Mechanisms, ANS - Complex Trait Genetics, and ACS - Pulmonary hypertension & thrombosis
Subjects: Models, Molecular, Male, 0301 basic medicine, Hydrolases, [SDV]Life Sciences [q-bio], Hippocampal formation, Medical and Health Sciences, 0302 clinical medicine, Neurodevelopmental disorder, Tubulin, Models, Neurotrophic factors, Cerebellum, Intellectual disability, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, dendrite branching, Genetics (clinical), de novo missense variants, Pediatric, Genetics & Heredity, DPYSL5, Biological Sciences, [SDV] Life Sciences [q-bio], corpus callosum agenesis, Mental Health, Child, Preschool, Neurological, Female, Microtubule-Associated Proteins, Adult, Neurite, Intellectual and Developmental Disabilities (IDD), primary neuronal cultures, Mutation, Missense, Biology, Young Adult, 03 medical and health sciences, Rare Diseases, Mediator, Report, Intellectual Disability, Genetics, medicine, Humans, Preschool, Corpus Callosum Agenesis, brain malformation, Neurosciences, Molecular, medicine.disease, neurodevelopmental disorder, Brain Disorders, 030104 developmental biology, Neurodevelopmental Disorders, Mutation, Missense, Agenesis of Corpus Callosum, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.
Published: 2021
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39. GestaltMatcher: Overcoming the limits of rare disease matching using facial phenotypic descriptors

Author: Malte Spielmann, Stéphane Bézieau, Elisabeth Mangold, Markus M. Nöthen, Peter Krawitz, Hartmut Engels, Nicole Fleischer, Matias Wagner, Axel Schmidt, Tobias B. Haack, Shahida Moosa, Alexej Knaus, Tzung-Chien Hsieh, Aviram Bar-Haim, Sugirthan Sivalingam, Martin-Atta Mensah, Stefan Mundlos, Nadja Ehmke, Karen W. Gripp, Denise Horn, Elke Krüger, Sébastien Küry, Theresa Brunet, Frédéric Ebstein, Christian P. Schaaf, Kathrin Grundmann-Hauser, Regina C. Betz, Martina Kreiß, Tom Kamphans, Claudia Perne, Sophia Peters, Magdalena Danyel, Heidi Beate Bentzen, Alexander Schmid, Guilherme Bonini, Kirsten Cremer, and Jean Tori Pantel
Subjects: Matching (statistics), Craniofacial abnormality, business.industry, Clinical diagnosis, Mutation (genetic algorithm), medicine, Computational biology, Medical diagnosis, medicine.disease, business, Phenotype, Convolutional neural network, Rare disease
Abstract: A large fraction of monogenic disorders causes craniofacial abnormalities with characteristic facial morphology. These disorders can be diagnosed more efficiently with the support of computer-aided next-generation phenotyping tools, such as DeepGestalt. These tools have learned to associate facial phenotypes with the underlying syndrome through training on thousands of patient photographs. However, this "supervised" approach means that diagnoses are only possible if the disorder was part of the training set. To improve recognition of ultra-rare disorders, we created GestaltMatcher, which uses a deep convolutional neural network based on the DeepGestalt framework. We used photographs of 17,560 patients with 1,115 rare disorders to define a "Clinical Face Phenotype Space". Distance between cases in the phenotype space defines syndromic similarity, allowing test patients to be matched to a molecular diagnosis even when the disorder was not included in the training set. Similarities among patients with previously unknown disease genes can also be detected. Therefore, in concert with mutation data, GestaltMatcher could accelerate the clinical diagnosis of patients with ultra-rare disorders and facial dysmorphism, as well as enable the delineation of novel phenotypes.
Published: 2021
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40. GestaltMatcher: Overcoming the limits of rare disease matching using facial phenotypic descriptors

Author: Tzung-Chien Hsieh, Aviram Bar-Haim, Shahida Moosa, Nadja Ehmke, Karen W. Gripp, Jean Tori Pantel, Magdalena Danyel, Martin Atta Mensah, Denise Horn, Stanislav Rosnev, Nicole Fleischer, Guilherme Bonini, Alexander Hustinx, Alexander Schmid, Alexej Knaus, Behnam Javanmardi, Hannah Klinkhammer, Hellen Lesmann, Sugirthan Sivalingam, Tom Kamphans, Wolfgang Meiswinkel, Frédéric Ebstein, Elke Krüger, Sébastien Küry, Stéphane Bézieau, Axel Schmidt, Sophia Peters, Hartmut Engels, Elisabeth Mangold, Martina Kreiß, Kirsten Cremer, Claudia Perne, Regina C. Betz, Tim Bender, Kathrin Grundmann-Hauser, Tobias B. Haack, Matias Wagner, Theresa Brunet, Heidi Beate Bentzen, Luisa Averdunk, Kimberly Christine Coetzer, Gholson J. Lyon, Malte Spielmann, Christian Schaaf, Stefan Mundlos, Markus M. Nöthen, and Peter Krawitz
Subjects: Phenotype, Rare Diseases, Artificial Intelligence, Face, Humans, Neural Networks, Computer, Article
Abstract: A large fraction of monogenic disorders causes craniofacial abnormalities with characteristic facial morphology. These disorders can be diagnosed more efficiently with the support of computer-aided next-generation phenotyping tools, such as DeepGestalt. These tools have learned to associate facial phenotypes with the underlying syndrome through training on thousands of patient photographs. However, this “supervised” approach means that diagnoses are only possible if the disorder was part of the training set. To improve recognition of ultra-rare disorders, we created GestaltMatcher, which uses a deep convolutional neural network based on the DeepGestalt framework. We used photographs of 17,560 patients with 1,115 rare disorders to define a “Clinical Face Phenotype Space”. Distance between cases in the phenotype space defines syndromic similarity, allowing test patients to be matched to a molecular diagnosis even when the disorder was not included in the training set. Similarities among patients with previously unknown disease genes can also be detected. Therefore, in concert with mutation data, GestaltMatcher could accelerate the clinical diagnosis of patients with ultra-rare disorders and facial dysmorphism, as well as enable the delineation of novel phenotypes.
Published: 2021
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41. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author: Bertrand Isidor, Ruth Armstrong, Thabo M. Yates, Susan M. White, Ruth Richardson, Solveig Heide, Katherine B. Burke, Tjitske Kleefstra, Marie Vincent, Meena Balasubramanian, Maria Irene Valenzuela Palafoll, Sébastien Küry, Rolph Pfundt, Ruth Newbury-Ecob, Sahar Mansour, Wendy K. Chung, Caroline Nava, Sofia Douzgou, Erika Leenders, Annachiara De Sandre-Giovannoli, Saba Sharif, Andrew E. Fry, Helen Stewart, Nicola K. Ragge, Alexander J. M. Dingemans, Pradeep C. Vasudevan, Alison Foster, Sahar Elouej, Shadi Albaba, François-Guillaume Debray, Boris Keren, Serwet Demirdas, Francis H. Sansbury, Thomas Scheffner, Arie van Haeringen, Alice S. Brooks, Meyke Schouten, Helen Cox, Kate Wilson, Sheffield Children's NHS Foundation Trust, University of Sheffield [Sheffield], Radboud University Medical Center [Nijmegen], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Birmingham Children’s Hospital, Manchester University NHS Foundation Trust (MFT), University of Manchester [Manchester], Addenbrooke's Hospital, Cambridge University NHS Trust, University Hospital of Wales, Oxford Brookes University, 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), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), 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)-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), St. George’s Hospital University, Oxford University Hospitals NHS Foundation Trust, Partenaires INRAE, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Columbia University [New York], Leiden University Medical Center (LUMC), Reutlingen University, Centre Hospitalier Universitaire de Liège (CHU-Liège), Murdoch Children's Research Institute (MCRI), University of Melbourne, Vall d'Hebron University Hospital [Barcelona], University Hospitals Bristol, Clinical Genetics, Institut Català de la Salut, [Balasubramanian M] Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. Academic Unit of Child Health, Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK. [Dingemans AJM] Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands. [Albaba S] Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. [Richardson R] Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Trust, Newcastle, UK. [Yates TM] Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. [Cox H] West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women’s and Children’s Hospitals NHS Foundation Trust, Birmingham, UK. [Palafoll MIV] Servei de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Grup de Recerca en Medicina Genètica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, University Hospital of Wales (UHW), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), and Universiteit Leiden
Subjects: Male, Pediatrics, Genetic testing, Developmental Disabilities, Craniofacial Abnormalities, Intellectual disability, Missense mutation, Child, Genetics (clinical), trastornos mentales::trastornos del desarrollo neurológico::discapacidades del desarrollo [PSIQUIATRÍA Y PSICOLOGÍA], 0303 health sciences, Otros calificadores::Otros calificadores::/genética [Otros calificadores], 030305 genetics & heredity, Cognition, Syndrome, Autism spectrum disorders, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Hypotonia, 3. Good health, Fenotip, Sin3 Histone Deacetylase and Corepressor Complex, Phenotype, Autism spectrum disorder, Child, Preschool, Cohort, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Trastorns del desenvolupament - Aspectes genètics, Infants, medicine.medical_specialty, Adolescent, personas::Grupos de Edad::niño [DENOMINACIONES DE GRUPOS], Article, 03 medical and health sciences, Mental Disorders::Neurodevelopmental Disorders::Developmental Disabilities [PSYCHIATRY AND PSYCHOLOGY], Intellectual Disability, Genetics, medicine, Other subheadings::Other subheadings::/genetics [Other subheadings], Humans, Attention deficit hyperactivity disorder, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Infant, Persons::Age Groups::Child [NAMED GROUPS], medicine.disease, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Genetic Phenomena::Phenotype [PHENOMENA AND PROCESSES], Autism, business, fenómenos genéticos::fenotipo [FENÓMENOS Y PROCESOS]
Abstract: Trastornos del espectro autista; Prueba genética Trastorns de l'espectre autista; Prova genètica Autism spectrum disorders; Genetic testing Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12. Funding for the project was provided by the Wellcome Trust and by grants from the Netherlands Organization for Health Research and Development (ZonMw grant 91718310 and the Dutch Scientific Organization (NWO, grant NWA 1160.18.320). WKC is supported by grants from SFARI and the JPB Foundation
Published: 2021
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42. Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Author: Tomi L. Toler, Timothy W. Yu, William B. Dobyns, Marcia C. Willing, Karen W. Gripp, Rolph Pfundt, Muhammad Iqbal, Xiadong Wang, Lance H. Rodan, Ada Hamosh, Cynthia S. Gubbels, Janice Baker, Thatjana Gardeitchik, Jenny Lai, André Reis, Fleur Vansenne, Jennifer E. Posey, Paranchai Boonsawat, Mathilde Nizon, Sébastien Küry, Jill R. Murrell, Julian L. Ambrus, Yunhong Wu, Laura A. Baker, Aubrie Soucy, Severine Audebert-Bellanger, Ellen van Binsbergen, Thomas Courtin, Guiseppe Zampino, Caleb P. Bupp, Holly K. Harris, Alan H. Beggs, Giulia Pascolini, Catharina (Nienke) M.L. Volker-Touw, Bert B.A. de Vries, Casie A. Genetti, La Donna L. Immken, Paola Grammatico, Martin Jakob Larsen, Sylvia Redon, Kévin Uguen, Reza Asadollahi, Madeleine Fannemel, Catherine Buchanan, Boris Keren, George E. Tiller, Lilian L. Cohen, Tojo Nakayama, Laurence E. Walsh, Iqra Ghulam Rasool, Audrey Labalme, Koen L.I. van Gassen, Pankaj B. Agrawal, Boxun Zhao, Gaetan Lesca, Steffan Syrbe, Kimberly A. Aldinger, Emanuele Agolini, Maria Kibaek, Muhammad Yasir Zahoor, Peter D. Turnpenny, Antonio Novelli, Ines Brösse, Claude Férec, Jorune Balciuniene, Nikoleta Argyrou, Victoria Suslovitch, Alice Poisson, Anita Rauch, Katelyn Payne, Christina Fagerberg, Cyril Mignot, Christopher Gray, Anne Blomhoff, Carolyn D. Applegate, Cornelia Kraus, Rami Abou Jamra, Marleen Simon, Martin Broly, Cara M. Skraban, and Emily Fassi
Subjects: Adult, 0301 basic medicine, Autism Spectrum Disorder, Regulatory Factor X Transcription Factors, 030105 genetics & heredity, Biology, Article, FRX, autism, intellectual disability, 03 medical and health sciences, Intellectual Disability, Ciliogenesis, Intellectual disability, mental disorders, medicine, Humans, Attention deficit hyperactivity disorder, Autistic Disorder, Gene, Genetics (clinical), Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], medicine.disease, Phenotype, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Attention Deficit Disorder with Hyperactivity, Autism spectrum disorder, Autism, RFX3, Transcription Factors
Abstract: Contains fulltext : 234024.pdf (Publisher’s version ) (Closed access) PURPOSE: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. METHODS: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. RESULTS: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. CONCLUSION: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Published: 2021
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43. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author: Stephanie J. Weinstein, Rami Nassir, Fredrick R. Schumacher, Neil Murphy, M. Henar Alonso, Satu Männistö, Hedy S. Rennert, Manish Gala, Phyllis J. Goodman, Albert de la Chapelle, Tilman Kühn, Fränzel J.B. Van Duijnhoven, Paul D.P. Pharoah, Anshul Kundaje, Juergen Boehm, W. James Gauderman, Mark A. Jenkins, Vittorio Perduca, Polly A. Newcomb, Amanda I. Phipps, Christopher I. Li, Douglas F. Easton, Antonia Trichopoulou, Kristin E. Anderson, Daniel D. Buchanan, Peter C. Scacheri, William M. Grady, Liher Imaz, Veronika Vymetalkova, Wan-Ling Hsu, Prudence R. Carr, Martha L. Slattery, Keith R. Curtis, Elizabeth A. Platz, Sai Chen, Graham G. Giles, D. Timothy Bishop, David M. Levine, Michael Hoffmeister, Duncan C. Thomas, Roger L. Milne, Michael O. Woods, Michael C. Bassik, Andrea Gsur, Dallas R. English, David V. Conti, Sébastien Küry, Wolfgang Lieb, Jochen Hampe, Coral Arnau-Collell, Steven Gallinger, Emily White, John S. Grove, Antoni Castells, Hermann Brenner, Amanda E. Toland, Noralane M. Lindor, Aurora Perez-Cornago, David Duggan, Temitope O. Keku, Edith J. M. Feskens, Heather Hampel, Korbinian Weigl, Li Li, Li Hsu, Conghui Qu, Peter T. Campbell, John L. Hopper, Volker Arndt, Jenny Chang-Claude, Lorena Moreno, John A. Baron, Stephen N. Thibodeau, Robert E. Schoen, Jeroen R. Huyghe, Rachel Pearlman, Sanford D. Markowitz, Amanda J. Cross, Stephan Buch, Barbara L. Banbury, Thomas J. Hudson, Yu Ru Su, Marc J. Gunter, Stephen B. Gruber, Heiner Boeing, Demetrius Albanes, Wen Yi Huang, Sergi Castellví-Bel, Jane C. Figueiredo, Catherine M. Tangen, Andrew T. Chan, Annika Lindblom, Deborah A. Nickerson, Richard B. Hayes, Lori C. Sakoda, Flavio Lejbkowicz, Salvatore Panico, Alicja Wolk, Kenneth Offit, John D. Potter, Leon Raskin, Bette J. Caan, Clemens Schafmayer, Mingyang Song, Lihong Qi, Elio Riboli, Hyun Min Kang, Sophia Harlid, Pavel Vodicka, Ludmila Vodickova, Cornelia M. Ulrich, Stephanie L. Schmit, Victor Moreno, Anna H. Wu, Brenda Diergaarde, Bethany Van Guelpen, Kala Visvanathan, Loic Le Marchand, Mazda Jenab, Amit Joshi, Stefanie Brezina, Stephanie A. Bien, Charles Kooperberg, Shuji Ogino, Daniela Seminara, Graham Casey, Andrea N. Burnett-Hartman, Robert W. Haile, Ulrike Peters, Gad Rennert, Tabitha A. Harrison, Ross L. Prentice, Yi Lin, Antonio Agudo, Gonçalo R. Abecasis, Sonja I. Berndt, Stephen J. Chanock, Stéphane Bézieau, Patrick S. Parfrey, Richard Barfield, Marie-Christine Boutron-Ruault, Huyghe, Jeroen R [0000-0001-6027-9806], Brenner, Hermann [0000-0002-6129-1572], Buchanan, Daniel D [0000-0003-2225-6675], Chan, Andrew T [0000-0001-7284-6767], Gsur, Andrea [0000-0002-9795-1528], Hampe, Jochen [0000-0002-2421-6127], Hoffmeister, Michael [0000-0002-8307-3197], Huang, Wen-Yi [0000-0002-4440-3368], Jenab, Mazda [0000-0002-0573-1852], Murphy, Neil [0000-0003-3347-8249], Peters, Ulrike [0000-0001-5666-9318], and Apollo - University of Cambridge Repository
Subjects: Male, 0301 basic medicine, Oncology, Candidate gene, Nutrition and Disease, Colorectal cancer, Genome-wide association study, Bioinformatics, medicine.disease_cause, Germline, colon carcinogenesis, Transcriptome, 0302 clinical medicine, Risk Factors, Voeding en Ziekte, Genotype, Age of Onset, Cecum, Aged, 80 and over, Gastroenterology, Middle Aged, cancer susceptibility, Primary tumor, Colon, Descending, 030220 oncology & carcinogenesis, Colonic Neoplasms, Female, Medical Genetics, Colon, Transverse, Adult, medicine.medical_specialty, Colon, cancer genetics, colorectal cancer, Biology, Polymorphism, Single Nucleotide, White People, Colon, Ascending, Genetic Heterogeneity, Young Adult, 03 medical and health sciences, Age Distribution, Medicina preventiva, genetic polymorphisms, Colon, Sigmoid, Càncer colorectal, Internal medicine, medicine, Genetics, Humans, Alleles, VLAG, Genetic association, Medicinsk genetik, Aged, Global Nutrition, Preventive medicine, Wereldvoeding, Cancer och onkologi, Gastroenterology & Hepatology, Rectal Neoplasms, Cancer, 1103 Clinical Sciences, medicine.disease, digestive system diseases, 030104 developmental biology, Cancer and Oncology, Case-Control Studies, 1114 Paediatrics and Reproductive Medicine, Human genome, Carcinogenesis, Genètica, Genome-Wide Association Study
Abstract: ObjectiveAn understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for sporadic CRC differs by anatomical subsite of the primary tumor has not been examined.DesignTo identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48,214 CRC cases and 64,159 controls of European ancestry. We characterized effect heterogeneity at CRC risk loci using multinomial modeling.ResultsWe identified 13 loci that reached genome-wide significance (P−8) and that were not reported by previous GWAS for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.ConclusionGenetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumor.Significance of this studyWhat is already known about this subject?Heterogeneity among colorectal cancer (CRC) tumors originating at different locations of the colorectum has been revealed in somatic genomes, epigenomes, and transcriptomes, and in some established environmental risk factors for CRC.Genome-wide association studies (GWAS) have identified over 100 genetic variants for overall CRC risk; however, a comprehensive analysis of the extent to which genetic risk factors differ by the anatomical sublocation of the primary tumor is lacking.What are the new findings?In this large consortium-based study, we analyzed clinical and genome-wide genotype data of 112,373 CRC cases and controls of European ancestry to comprehensively examine whether CRC case subgroups defined by anatomical sublocation have distinct germline genetic etiologies.We discovered 13 new loci at genome-wide significance (P−8) that were specific to certain anatomical sublocations and that were not reported by previous GWAS for overall CRC risk; multiple lines of evidence support strong candidate target genes at several of these loci, including PTGER3, LCT, MLH1, CDX1, KLF14, PYGL, BCL11B, and BMP7.Systematic heterogeneity analysis of genetic risk variants for CRC identified thus far, revealed that the genetic architectures of proximal and distal CRC are partly distinct.Taken together, our results further support the idea that tumors arising in different anatomical sublocations of the colorectum may have distinct etiologies.How might it impact on clinical practice in the foreseeable future?Our results provide an informative resource for understanding the differential role that genes and pathways may play in the mechanisms of proximal and distal CRC carcinogenesis.The new insights into the etiologies of proximal and distal CRC may inform the development of new precision prevention strategies, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention.Our findings suggest that future studies of etiological risk factors for CRC and molecular mechanisms of carcinogenesis should take into consideration the anatomical sublocation of the colorectal tumor.
Published: 2021

44. Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons

Author: Corinne Beurrier, Karen Runge, Sylvie Giacuzz, Rémi Mathieu, Saadet Mercimek-Andrews, Laurent Fasano, Nenad Sestan, Sandra Goebbels, Antoinette Gelot, Lauren Jeffries, Gabriel Santpere, Jill A. Rosenfeld, Carlos Cardoso, Dina Amrom, Candace Gamble, Stéphane Bugeon, Chana Ratner, Antoine de Chevigny, Harold Cremer, Sahra Lafi, Audrey Van Hecke, Kristin Lindstrom, Arie van Haeringen, Sébastien Küry, Emilie Pallesi-Pocachard, Eva Hudson, Olivier Vanakker, Léonard Hérault, Arthur Loubat, Andreas Bosio, Bernard Jacq, Aurélie Montheil, Belen Lorente-Galdos, Fabienne Schaller, Stephane Gaillard, Surajit Sahu, Alfonso Represa, Reena Jethva, pellegrino, Christophe, Blanc 2013 - Contrôle moléculaire de la neurogenèse postnatale : génes et microRNAs - - AtmiR2013 - ANR-13-BSV4-0013 - Blanc 2013 - VALID, Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Theories and Approaches of Genomic Complexity (TAGC), Phenotype-expertise, Miltenyi Biotec, Department of Research and Development, Baylor College of Medicine (BCM), Baylor University, UNT Health Science Center [Fort Worth, USA], University of North Texas (UNT), Phoenix Children's Hospital, University of Alberta, Yale School of Medicine [New Haven, Connecticut] (YSM), Leiden University Medical Center (LUMC), Ghent University Hospital, Children's University Hospital Queen Fabiola [Bruxelles, Belgium], Université libre de Bruxelles (ULB), Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hackensack University Medical Center [Hackensack], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Max Planck Institute of Experimental Medicine [Göttingen] (MPI), Max-Planck-Gesellschaft, ANR-13-BSV4-0013,AtmiR,Contrôle moléculaire de la neurogenèse postnatale : génes et microRNAs(2013), Universiteit Leiden, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Yale University School of Medicine, and CHU de Nantes, l'Institut du Thorax, CIC
Subjects: 0301 basic medicine, Nervous system, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biology, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, Epilepsy, Glutamatergic, Prosencephalon, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Basic Helix-Loop-Helix Transcription Factors, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Autistic Disorder, Molecular Biology, Cerebral Cortex, Neurons, Neuropeptides, Biologie moléculaire, Autism spectrum disorders, medicine.disease, Psychiatry and Mental health, 030104 developmental biology, medicine.anatomical_structure, Cerebral cortex, Forebrain, Autism, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Immediate Communication, Sciences cognitives, Neuroscience, 030217 neurology & neurosurgery, Psychiatrie, Transcription Factors
Abstract: While the transcription factor NEUROD2 has recently been associated with epilepsy, its precise role during nervous system development remains unclear. Using a multi-scale approach, we set out to understand how Neurod2 deletion affects the development of the cerebral cortex in mice. In Neurod2 KO embryos, cortical projection neurons over-migrated, thereby altering the final size and position of layers. In juvenile and adults, spine density and turnover were dysregulated in apical but not basal compartments in layer 5 neurons. Patch-clamp recordings in layer 5 neurons of juvenile mice revealed increased intrinsic excitability. Bulk RNA sequencing showed dysregulated expression of many genes associated with neuronal excitability and synaptic function, whose human orthologs were strongly associated with autism spectrum disorders (ASD). At the behavior level, Neurod2 KO mice displayed social interaction deficits, stereotypies, hyperactivity, and occasionally spontaneous seizures. Mice heterozygous for Neurod2 had similar defects, indicating that Neurod2 is haploinsufficient. Finally, specific deletion of Neurod2 in forebrain excitatory neurons recapitulated cellular and behavioral phenotypes found in constitutive KO mice, revealing the region-specific contribution of dysfunctional Neurod2 in symptoms. Informed by these neurobehavioral features in mouse mutants, we identified eleven patients from eight families with a neurodevelopmental disorder including intellectual disability and ASD associated with NEUROD2 pathogenic mutations. Our findings demonstrate crucial roles for Neurod2 in neocortical development, whose alterations can cause neurodevelopmental disorders including intellectual disability and ASD., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2021
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45. Disruption of the transcription factor NEUROD2 causes an autism syndrome via cell-autonomous defects in cortical projection neurons

Author: Aurélie Montheil, Saadet Mercimek-Andrews, Bruno Pichon, Stéphane Bugeon, Léonard Hérault, Gabriel Santpere, Emilie Pallesi-Pocachard, Carlos Cardoso, Harold Cremer, Fabienne Schaller, Eva Hudson, Sahra Lafi, Antoinette Gelot, Karen Runge, Sylvie Giacuzzo, Rémi Mathieu, Kristin Lindstrom, Arie van Haeringen, Stephane Gaillard, Laurent Fasano, Antoine de Chevigny, Dina Amrom, Jill A. Rosenfeld, Bernard Jacq, Candace Gamble, Nenad Sestan, Surajit Sahu, Alfonso Represa, Belen Lorente-Galdos, Arthur Loubat, Andreas Bosio, Lauren Jeffries, Olivier Vanakker, Mélanie Cahuc, Audrey Van Hecke, Sébastien Küry, Corinne Beurrier, Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0303 health sciences, Mutation, Dendritic spine, Biology, medicine.disease_cause, medicine.disease, Phenotype, 03 medical and health sciences, 0302 clinical medicine, NEUROD2, Forebrain, medicine, Excitatory postsynaptic potential, Autism, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, Transcription factor, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: We identified seven families associatingNEUROD2pathogenic mutations with ASD and intellectual disability. To get insight into the pathophysiological mechanisms, we analyzed cortical development inNeurod2KO mice. Cortical projection neurons (CPNs) over-migrated during embryogenesis, inducing abnormal thickness and laminar positioning of cortical layers. At juvenile ages, dendritic spine turnover and intrinsic excitability were increased in L5 CPNs. Differentially expressed genes inNeurod2KO mice were enriched for voltage-gated ion channels, and the human orthologs of these genes were strongly associated with ASD. Furthermore, adultNeurod2KO mice exhibited core ASD-like behavioral abnormalities. Finally, by generatingNeurod2conditional mutant mice we demonstrate that forebrain excitatory neuron-specificNeurod2deletion recapitulates cellular and behavioral ASD phenotypes found in full KO mice. Our findings demonstrate crucial roles forNeurod2in cortical development and function, whose alterations likely account for ASD and related symptoms in the newly definedNEUROD2mutation syndrome.
Published: 2020

46. Cumulative Burden of Colorectal Cancer–Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer

Author: Ludmila Vodickova, Douglas A. Corley, Phyllis J. Goodman, Albert de la Chapelle, Cornelia M. Ulrich, Gianluca Severi, Alexi N. Archambault, Douglas F. Easton, Stephanie L. Schmit, Victor Moreno, Tilman Kühn, Fredrick R. Schumacher, D. Timothy Bishop, Sonja I. Berndt, Domenico Palli, Fränzel J.B. Van Duijnhoven, Jose E. Castelao, Mingyang Song, Anna H. Wu, Wen Yi Huang, Sergi Castellví-Bel, Ulrike Peters, Stephen J. Chanock, Sanford D. Markowitz, Heather Hampel, Jenny Chang-Claude, Andrea Gsur, Stephanie J. Weinstein, Edith J. M. Feskens, Christopher A. Haiman, Mengmeng Du, Melissa C. Southey, John A. Baron, Bethany Van Guelpen, Kala Visvanathan, Loic Le Marchand, Victor Muñoz-Garzón, Ellen Kampman, Andrea N. Burnett-Hartman, Polly A. Newcomb, Paul D.P. Pharoah, Erin M. Siegel, Mark A. Jenkins, Gad Rennert, Tabitha A. Harrison, Neil Murphy, Antonia Trichopoulou, Sébastien Küry, Elizabeth L. Barry, Stephan Buch, Jochen Hampe, Minta Thomas, Vicente Martín, Michael O. Woods, Demetrius Albanes, Jeroen R. Huyghe, Robert S. Sandler, Li Hsu, Emily White, John L. Hopper, Rachel Pearlman, Peter T. Campbell, Peter S. Liang, Yin Cao, Amanda J. Cross, Graham G. Giles, Robert E. Schoen, Robert J. MacInnis, David Duggan, Michael Hoffmeister, Corinne E. Joshu, Christopher K. Edlund, Elizabeth A. Platz, Liesel M. FitzGerald, Anne Zeleniuch-Jacquotte, Hermann Brenner, Heinz-Josef Lenz, Lori C. Sakoda, Jane C. Figueiredo, Yu Ru Su, Stephen B. Gruber, Satu Männistö, Stephen N. Thibodeau, Christoph Mancao, Dallas R. English, Thomas J. Hudson, Li Li, John D. Potter, Andreana N. Holowatyj, David V. Conti, Temitope O. Keku, Sophia Harlid, Eric J. Jacobs, Jihyoun Jeon, Amit Joshi, Clemens Schafmayer, Pavel Vodicka, Leticia Moreira, María Dolores Chirlaque, Yi Lin, David J. Hunter, Michelle Cotterchio, Martha L. Slattery, Alicja Wolk, Roger L. Milne, Marc J. Gunter, Susanna C. Larsson, Annika Lindblom, Graham Casey, Christopher I. Li, Aung Ko Win, Ban Younghusband, Stefanie Brezina, Stephanie A. Bien, Lynne R. Wilkens, Daniela Seminara, Daniel D. Buchanan, Stéphane Bézieau, Manuela Gago-Dominguez, Patrick S. Parfrey, Hedy S. Rennert, Ann G. Zauber, Elisabeth F.P. Peterse, Faye Elliott, Catherine M. Tangen, Andrew T. Chan, Richard B. Hayes, Steven Gallinger, Amanda E. Toland, Noralane M. Lindor, María José Sánchez, Korbinian Weigl, Kenneth Offit, Iris Lansdorp-Vogelaar, Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, and Public Health
Subjects: 0301 basic medicine, Oncology, Male, COLONOSCOPY, Genotyping Techniques, Nutrition and Disease, DNA Mutational Analysis, Datasets as Topic, Penetrance, HEREDITARY, Cohort Studies, 0302 clinical medicine, Mutation Rate, Risk Factors, Voeding en Ziekte, Family history, Age of Onset, Medical History Taking, education.field_of_study, Colon Cancer, HERITABILITY, Gastroenterology, Middle Aged, Lynch syndrome, Cohort, 030211 gastroenterology & hepatology, Female, Colorectal Neoplasms, Life Sciences & Biomedicine, EOCRC, Cohort study, medicine.medical_specialty, EPIDEMIOLOGY RESEARCH, Population, SNP, LYNCH-SYNDROME, Polymorphism, Single Nucleotide, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Life Style, VLAG, Global Nutrition, Wereldvoeding, Science & Technology, Hepatology, Gastroenterology & Hepatology, Whole Genome Sequencing, business.industry, MUTATIONS, Case-control study, Cancer, 1103 Clinical Sciences, Odds ratio, medicine.disease, digestive system diseases, 030104 developmental biology, Case-Control Studies, LOW-PENETRANCE SUSCEPTIBILITY, 1114 Paediatrics and Reproductive Medicine, ADULT HEALTH, RACE/ETHNICITY, business, 1109 Neurosciences, Genome-Wide Association Study
Abstract: BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
Published: 2020

47. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor beta Signaling

Author: Brett V. Johnson, Raman Kumar, Sabrina Oishi, Suzy Alexander, Maria Kasherman, Michelle Sanchez Vega, Atma Ivancevic, Alison Gardner, Deepti Domingo, Mark Corbett, Euan Parnell, Sehyoun Yoon, Tracey Oh, Matthew Lines, Henrietta Lefroy, Usha Kini, Margot Van Allen, Sabine Grønborg, Sandra Mercier, Sébastien Küry, Stéphane Bézieau, Laurent Pasquier, Martine Raynaud, Alexandra Afenjar, Thierry Billette de Villemeur, Boris Keren, Julie Désir, Lionel Van Maldergem, Martina Marangoni, Nicola Dikow, David A. Koolen, Peter M. VanHasselt, Marjan Weiss, Petra Zwijnenburg, Joaquim Sa, Claudia Falcao Reis, Carlos López-Otín, Olaya Santiago-Fernández, Alberto Fernández-Jaén, Anita Rauch, Katharina Steindl, Pascal Joset, Amy Goldstein, Suneeta Madan-Khetarpal, Elena Infante, Elaine Zackai, Carey Mcdougall, Vinodh Narayanan, Keri Ramsey, Saadet Mercimek-Andrews, Loren Pena, Vandana Shashi, Kelly Schoch, Jennifer A. Sullivan, Filippo Pinto e Vairo, Pavel N. Pichurin, Sarah A. Ewing, Sarah S. Barnett, Eric W. Klee, M. Scott Perry, Mary Kay Koenig, Catherine E. Keegan, Jane L. Schuette, Stephanie Asher, Yezmin Perilla-Young, Laurie D. Smith, Jill A. Rosenfeld, Elizabeth Bhoj, Paige Kaplan, Dong Li, Renske Oegema, Ellen van Binsbergen, Bert van der Zwaag, Marie Falkenberg Smeland, Ioana Cutcutache, Matthew Page, Martin Armstrong, Angela E. Lin, Marcie A. Steeves, Nicolette den Hollander, Mariëtte J.V. Hoffer, Margot R.F. Reijnders, Serwet Demirdas, Daniel C. Koboldt, Dennis Bartholomew, Theresa Mihalic Mosher, Scott E. Hickey, Christine Shieh, Pedro A. Sanchez-Lara, John M. Graham, Kamer Tezcan, G.B. Schaefer, Noelle R. Danylchuk, Alexander Asamoah, Kelly E. Jackson, Naomi Yachelevich, Margaret Au, Luis A. Pérez-Jurado, Tjitske Kleefstra, Peter Penzes, Stephen A. Wood, Thomas Burne, Tyler Mark Pierson, Michael Piper, Jozef Gécz, Lachlan A. Jolly, Maria T. Acosta, David R. Adams, Aaron Aday, Mercedes E. Alejandro, Patrick Allard, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Deborah Barbouth, Gabriel F. Batzli, Alan H. Beggs, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Stephanie Bivona, Carsten Bonnenmann, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lauren C. Briere, Elly Brokamp, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Olveen Carrasquillo, Ta Chen Peter Chang, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D'Souza, Surendra Dasari, Mariska Davids, Jean M. Davidson, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Annika M. Dries, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Gregory M. Enns, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Noah D. Friedman, William A. Gahl, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Jean-Philippe F. Gourdine, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Frances High, Ingrid A. Holm, Jason Hom, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Lefkothea Karaviti, Emily G. Kelley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Byron Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Ronit Marom, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Jason D. Merker, Thomas O. Metz, Matthew Might, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Devin Oglesbee, James P. Orengo, Stephen Pak, J. Carl Pallais, Christina GS. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Genecee Renteri, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Robb K. Rowley, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Kathleen Shields, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, David A. Sweetser, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Tiphanie P. Vogel, Daryl M. Waggott, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Daniel Wegner, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Elizabeth A. Worthey, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, Stephan Zuchner, William Gahl, Clinical Genetics, Human genetics, Amsterdam Reproduction & Development (AR&D), ACS - Atherosclerosis & ischemic syndromes, MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output
Subjects: Male, 0301 basic medicine, Brain malformation, Developmental Disabilities, INTERACTS, USP9X, Haploinsufficiency, in-vitro, CELL-MIGRATION, Deubiquitylating enzyme, Biology, Hippocampus, of-function mutations, Article, liquid facets, TGFβ, Mice, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, TGF beta, Transforming Growth Factor beta, Intellectual Disability, Intellectual disability, medicine, Animals, Humans, Missense mutation, deubiquitinating enzyme, Biological Psychiatry, fam/usp9x, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Male Phenotype, medicine.disease, Phenotype, Hypotonia, 030104 developmental biology, Female, medicine.symptom, Ubiquitin Thiolesterase, Neuroscience, 030217 neurology & neurosurgery, Signal Transduction, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Transforming growth factor
Abstract: Contains fulltext : 218305.pdf (Publisher’s version ) (Closed access) BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor beta signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hippocampal function.
Published: 2020
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48. Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia

Author: Benjamin Cogné, Stephen Sanders, François Rivier, Tahir N. Khan, Mireille Claustres, Gaetan Lesca, Lihadh Al-Gazali, Annick Vogels, Sarah Weckhuysen, Nicholas Katsanis, Stéphane Bézieau, Thomas Besnard, Maxime Cadieux-Dion, Julitta de Bellescize, Katrin Õunap, Anne Boland, Aurora Pujol, Monica H. Wojcik, Maria J. Guillen Sacoto, Paul Rollier, Laurent Pasquier, Bertrand Isidor, Sébastien Küry, Hilde Van Esch, Aisha Al Shamsi, Megan T. Cho, Kyle Retterer, Michel Koenig, Christèle Dubourg, Andreas G. Chiocchetti, Damien Sanlaville, Erica E. Davis, Claire Guissart, Sander Pajusalu, Hannah Stamberger, Xenia Latypova, Shannon Sattler, Souphatta Sasorith, Isabelle Thiffault, Marie Vincent, Nicolas Leboucq, Irman Forghani, Lynn Schema, Sylvie Odent, Marie T. McDonald, Lauren E. Grote, Susanne Kjaergaard, Wilfrid Carré, Rena Pressman, Emily G. Farrow, Jean-François Deleuze, Carol J Saunders, Deborah Barbouth, Danielle Karlowicz, Nicole P. Safina, Kirsty McWalter, Christine M. Freitag, Wim Van Paesschen, Rebecca Willaert, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical Genetics, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Universitätsklinikum Leipzig, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Human Molecular Genetics, Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de biologie moléculaire, Hôpital Pontchaillou, Centre National de Genotypage, Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Pediatrics, Faculty of Medicine and Health Sciences, UAE University, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de Neuroradiologie[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Service de Génétique, Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Center for Human Disease Modeling, Duke University [Durham], Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Service de génétique clinique, hôpital Sud, National Human Genome Research Institute, UM1 HG008900, National Eye Institute, PUT355, Eesti Teadusagentuur, 2011-RARE-004-01, Agence Nationale pour la Recherche/E-rare Joint-Transnational-Call 2011, National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program, R01 MH106826, NIH, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), and Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud
Subjects: Male, 0301 basic medicine, Autism, [SDV]Life Sciences [q-bio], Neurodegenerative, Medical and Health Sciences, RORA, Purkinje Cells, 0302 clinical medicine, Neurodevelopmental disorder, Group F, 80 and over, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, Zebrafish, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Genes, Dominant, Pediatric, Genetics & Heredity, Aged, 80 and over, Genetics, Malalties neurodegeneratives, Brain, Nuclear Receptor Subfamily 1, Group F, Member 1, Neurodegenerative Diseases, Syndrome, Biological Sciences, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Mental Health, intellectual disability, Child, Preschool, Larva, Neurological, Female, Cerebellar atrophy, medicine.symptom, Haploinsufficiency, Adult, Member 1, Ataxia, Cerebellar Ataxia, Nuclear Receptor Subfamily 1, Adolescent, DNA Copy Number Variations, Intellectual and Developmental Disabilities (IDD), Mutation, Missense, Biology, Article, 03 medical and health sciences, Rare Diseases, medicine, Animals, Humans, Dominant, Autistic Disorder, Allele, Preschool, Alleles, Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cerebellar ataxia, Animal, Point mutation, Genetic Complementation Test, Neurosciences, medicine.disease, neurodevelopmental disorder, Brain Disorders, Disease Models, Animal, 030104 developmental biology, Genes, autistic features, Disease Models, Mutation, epilepsy, Human medicine, cerebellar ataxia, Missense, Autisme, dual molecular effects, 030217 neurology & neurosurgery
Abstract: RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome. ispartof: American Journal of Human Genetics vol:102 issue:5 pages:744-759 ispartof: location:United States status: published
Published: 2018
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49. De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Author: Naomi Meeks, Stefan Kindler, Anya Revah-Politi, Alexander P.A. Stegmann, Vinodh Narayanan, Dominique Bonneau, Claudia Schob, Jill A. Rosenfeld, Jennifer E. Posey, Tim M. Strom, LaDonna Immken, Tjitske Kleefstra, Jolanda H. Schieving, Katherine L. Helbig, Estelle Colin, Magalie Barth, Tamar Harel, Matthew J. Huentelman, James R. Lupski, Benjamin Cogné, Han G. Brunner, Yaping Yang, Sébastien Küry, Jenny Morton, Erica H. Gerkes, Keri Ramsey, Marine Tessarech, Zeynep Coban-Akdemir, Shimon Edvardson, Hans-Jürgen Kreienkamp, Nelly Oundjian, Davor Lessel, Christian Kubisch, Thomas Besnard, Jonas Denecke, Orly Elpeleg, Ana M. Claasen, Kelsey Zegar, Mohammad K. Eldomery, Sandra Mercier, Margot R.F. Reijnders, Stéphane Bézieau, Univ Angers, Okina, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Central Nervous System, Male, DISRUPTION, INTELLECTUAL DISABILITY, Developmental Disabilities, PROTEIN, DISEASE, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Missense mutation, Global developmental delay, Amino Acids, Child, Genetics (clinical), Genetics, Adenosine Triphosphatases, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Translation (biology), Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, FAMILY, Child, Preschool, Female, RNA Helicases, MODULE, Adolescent, Mutation, Missense, RNA GRANULES, Biology, Article, Cell Line, 03 medical and health sciences, Stress granule, Cell Line, Tumor, medicine, Humans, HELICASE, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], STRESS GRANULES, Helicase, RNA, Correction, medicine.disease, GENE, 030104 developmental biology, HEK293 Cells, biology.protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Contains fulltext : 182457.pdf (Publisher’s version ) (Open Access) DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.
Published: 2017
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50. Characterization of zinc amino acid complexes for zinc delivery in vitro using Caco-2 cells and enterocytes from hiPSC

Author: Ann Katrin Sauer, Simone Hagmeyer, Ann-Kathrin Mattes, Franziska Briel, Laura Tarana, Andreas M. Grabrucker, Stefanie Pfaender, Sébastien Küry, and Tobias M. Boeckers
Subjects: 0301 basic medicine, Enterocyte, Acrodermatitis enteropathica, Induced Pluripotent Stem Cells, Primary Cell Culture, chemistry.chemical_element, Biological Availability, Zinc, General Biochemistry, Genetics and Molecular Biology, Article, Absorption, Biomaterials, 03 medical and health sciences, Mice, Coordination Complexes, medicine, Animals, Humans, Gastro-intestinal, Amino Acids, chemistry.chemical_classification, Zip4, 030109 nutrition & dietetics, Acrodermatitis, Metals and Alloys, Biological Transport, Cell Differentiation, medicine.disease, In vitro, Amino acid, Bioavailability, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Enterocytes, Biochemistry, chemistry, Caco-2, Female, Caco-2 Cells, General Agricultural and Biological Sciences, hIPSC, Carrier Proteins, Intracellular
Abstract: Zn is essential for growth and development. The bioavailability of Zn is affected by several factors such as other food components. It is therefore of interest, to understand uptake mechanisms of Zn delivering compounds to identify ways to bypass the inhibitory effects of these factors. Here, we studied the effect of Zn amino acid conjugates (ZnAAs) on the bioavailabilty of Zn. We used Caco-2 cells and enterocytes differentiated from human induced pluripotent stem cells from a control and Acrodermatitis enteropathica (AE) patient, and performed fluorescence based assays, protein biochemistry and atomic absorption spectrometry to characterize cellular uptake and absorption of ZnAAs. The results show that ZnAAs are taken up by AA transporters, leading to an intracellular enrichment of Zn mostly uninhibited by Zn uptake antagonists. Enterocytes from AE patients were unable to gain significant Zn through exposure to ZnCl2 but did not show differences with respect to ZnAAs. We conclude that ZnAAs may possess an advantage over classical Zn supplements such as Zn salts, as they may be able to increase bioavailability of Zn, and may be more efficient in patients with AE. Electronic supplementary material The online version of this article (doi:10.1007/s10534-017-0033-y) contains supplementary material, which is available to authorized users.
Published: 2017

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