Author: "Sébastien Jacquemont" / Topic: genetics - Searchworks@Jio Institute Digital Library Search Results

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1. P822: Navigating genetic risk: Mapping variant's probability of occurring de novo and inferring their effect sizes on neurodevelopmental symptoms

Author: Jade England, Guillaume Huguet, Khadijé Jizi, Cécile Poulain, Élise Douard, Zohra Saci, Catalina Maftei, Emmanuelle Lemyre, and Sébastien Jacquemont
Subjects: Genetics, QH426-470, Medicine
Published: 2024
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2. Copy Number Variation and Structural Genomic Findings in 116 Cases of Sudden Unexplained Death between 1 and 28 Months of Age

Author: Catherine A. Brownstein, Elise Douard, Robin L. Haynes, Hyun Yong Koh, Alireza Haghighi, Christine Keywan, Bree Martin, Sanda Alexandrescu, Elisabeth A. Haas, Sara O. Vargas, Monica H. Wojcik, Sébastien Jacquemont, Annapurna H. Poduri, Richard D. Goldstein, and Ingrid A. Holm
Subjects: autism spectrum disorder, chromosomal microarray, death, genetics, genomics, sudden infant death syndrome, Genetics, QH426-470
Abstract: Abstract In sudden unexplained death in pediatrics (SUDP) the cause of death is unknown despite an autopsy and investigation. The role of copy number variations (CNVs) in SUDP has not been well‐studied. Chromosomal microarray (CMA) data are generated for 116 SUDP cases with age at death between 1 and 28 months. CNVs are classified using the American College of Medical Genetics and Genomics guidelines and CNVs in our cohort are compared to an autism spectrum disorder (ASD) cohort, and to a control cohort. Pathogenic CNVs are identified in 5 of 116 cases (4.3%). Variants of uncertain significance (VUS) favoring pathogenic CNVs are identified in 9 cases (7.8%). Several CNVs are associated with neurodevelopmental phenotypes including seizures, ASD, developmental delay, and schizophrenia. The structural variant 47,XXY is identified in two cases (2/69 boys, 2.9%) not previously diagnosed with Klinefelter syndrome. Pathogenicity scores for deletions are significantly elevated in the SUDP cohort versus controls (p = 0.007) and are not significantly different from the ASD cohort. The finding of pathogenic or VUS favoring pathogenic CNVs, or structural variants, in 12.1% of cases, combined with the observation of higher pathogenicity scores for deletions in SUDP versus controls, suggests that CMA should be included in the genetic evaluation of SUDP.
Published: 2023
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3. Stability of polygenic scores across discovery genome-wide association studies

Author: Laura M. Schultz, Alison K. Merikangas, Kosha Ruparel, Sébastien Jacquemont, David C. Glahn, Raquel E. Gur, Ran Barzilay, and Laura Almasy
Subjects: PTSD, height, type 2 diabetes, Philadelphia Neurodevelopmental Cohort, Adolescent Brain Cognitive Development study, PRS-CS, Genetics, QH426-470
Abstract: Summary: Polygenic scores (PGS) are commonly evaluated in terms of their predictive accuracy at the population level by the proportion of phenotypic variance they explain. To be useful for precision medicine applications, they also need to be evaluated at the individual level when phenotypes are not necessarily already known. We investigated the stability of PGS in European American (EUR) and African American (AFR)-ancestry individuals from the Philadelphia Neurodevelopmental Cohort and the Adolescent Brain Cognitive Development study using different discovery genome-wide association study (GWAS) results for post-traumatic stress disorder (PTSD), type 2 diabetes (T2D), and height. We found that pairs of EUR-ancestry GWAS for the same trait had genetic correlations >0.92. However, PGS calculated from pairs of same-ancestry and different-ancestry GWAS had correlations that ranged from
Published: 2022
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4. Epigenotype-genotype–phenotype correlations in SETD1A and SETD2 chromatin disorders

Author: Sunwoo Lee, Lara Menzies, Eleanor Hay, Eguzkine Ochoa, France Docquier, Fay Rodger, Charu Deshpande, Nicola C Foulds, Sébastien Jacquemont, Khadije Jizi, Henriette Kiep, Alison Kraus, Katharina Löhner, Patrick J Morrison, Bernt Popp, Ruth Richardson, Arie Haeringen, Ezequiel Martin, Ana Toribio, Fudong Li, Wendy D Jones, Francis H Sansbury, and Eamonn R Maher
Subjects: Genetics, General Medicine, Molecular Biology, Genetics (clinical)
Abstract: Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterised by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next generation sequencing based assay. Comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. Review of the clinical and genetic features of SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants (p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)). Both SETD2 subgroups demonstrated a methylation episignature which was characterised by hypomethylation and hypermethylation events respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype–phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.
Published: 2023

5. Rare and common autism risk variants converge across 16p

Author: Hyejung Won, Guillaume Huguet, and Sébastien Jacquemont
Subjects: Autism Spectrum Disorder, Genetics, Humans, Genetic Predisposition to Disease, Autistic Disorder, Polymorphism, Single Nucleotide
Published: 2022

6. Structural and functional brain alterations revealed by neuroimaging in CNV carriers

Author: Christopher R.K. Ching, Carrie E. Bearden, Clara Moreau, Sébastien Jacquemont, Kuldeep Kumar, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre Hospitalier Universitaire Sainte Justine (CHU Sainte Justine), Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Keck School of Medicine [Los Angeles], University of Southern California (USC), Semel Institute for Neuroscience and Human Behavior [Los Angeles, Ca], University of California [Los Angeles] (UCLA), University of California-University of California, This work was supported by Calcul Quebec (http://www.calculquebec.ca) and Compute Canada (http://www.computecanada.ca), the Brain Canada Multi-Investigator initiative, the Canadian Institutes of Health Research, CIHR_400528, The Institute of Data Valorization (IVADO) through the Canada First Research Excellence Fund, Healthy Brains for Healthy Lives through the Canada First Research Excellence Fund, and the National Institute of Mental Health (grants R01MH085953, R21MH116473, and 9U01MH119736-02).Dr Jacquemont is a recipient of a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. Kuldeep Kumar was supported by The Institute of Data Valorization (IVADO) Postdoctoral Fellowship program, through the Canada First Research Excellence Fund. CRKC was supported by NIAT32AG058507 and U54EB020403 from the Big Data to Knowledge (BD2K) Program., We wish to thank Sophia Thomopoulos for her assistance with accessing effect size data from the published ENIGMA studies for Figure 2. We also thank the ENIGMA 22q11.2 Deletion Syndrome Working Group (http://enigma.ini.usc.edu/ongoing/enigma-22q-working-group/) and CNV Working Group members (http://enigma.ini.usc.edu/ongoing/enigma-cnv/) for their contributions to these large-scale collaborative studies., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Sainte Justine [Montréal], and University of California (UC)-University of California (UC)
Subjects: DNA Copy Number Variations, Endophenotypes, Population, Neuroimaging, Genomics, Computational biology, Biology, Article, 03 medical and health sciences, Functional brain, 0302 clinical medicine, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Copy-number variation, Aetiology, education, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, education.field_of_study, Mental Disorders, [SCCO.NEUR]Cognitive science/Neuroscience, Human Genome, Neurosciences, Brain, Brain Disorders, 3. Good health, Mental Health, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Endophenotype, Neurological, Patient Safety, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract: International audience; Copy Number Variants (CNVs) are associated with elevated rates of neuropsychiatric disorders. A 'genetics-first' approach, involving the CNV effects on the brain, irrespective of clinical symptomatology, allows investigation of mechanisms underlying neuropsychiatric disorders in the general population. Recent years have seen an increasing number of larger multisite neuroimaging studies investigating the effect of CNVs on structural and functional brain endophenotypes. Alterations overlap with those found in idiopathic psychiatric conditions but effect sizes are twofold to fivefold larger. Here we review new CNV-associated structural and functional brain alterations and outline the future of neuroimaging genomics research, with particular emphasis on developing new resources for the study of high-risk CNVs and rare genomic variants.
Published: 2021

7. Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts

Author: Giuliana, Giannuzzi, Nicolas, Chatron, Katrin, Mannik, Chiara, Auwerx, Sylvain, Pradervand, Gilles, Willemin, Kendra, Hoekzema, Xander, Nuttle, Jacqueline, Chrast, Sadler, Marie C., Eleonora, Porcu, Katrin, Männik, Damien, Sanlaville, Caroline, Schluth-Bolard, Cédric Le Caignec, Mathilde, Nizon, Sandra, Martin, Sébastien, Jacquemont, Armand, Bottani, Marion, Gérard, Sacha, Weber, Aurélia, Jacquette, Catherine, Vincent-Delorme, Aurora, Currò, Francesca, Mari, Alessandra, Renieri, Brusco, Alfredo, Ferrero, Giovanni Battista, Yann, Herault, Bertrand, Isidor, Brigitte, Gilbert-Dussardier, Eichler, Evan E., Zoltan, Kutalik, Alexandre, Reymond, 16p11.2 Consortium, Männik, K., Sanlaville, D., Schluth-Bolard, C., Le Caignec, C., Nizon, M., Martin, S., Jacquemont, S., Bottani, A., Gérard, M., Weber, S., Jacquette, A., Vincent-Delorme, C., Currò, A., Mari, F., Renieri, A., Brusco, A., and Ferrero, G.B.
Subjects: BOLA2, neurodevelopmental disease, Recurrent copy-number variations, CNV, 16p11.2, BOLA2, neurodevelopmental disease, neutropenia, lymphopenia, CNV, Genetics, neutropenia, lymphopenia, 16p11.2, Recurrent copy-number variations, Molecular Biology, Genetics (clinical)
Abstract: Recurrent copy-number variations (CNVs) at chromosome 16p11.2 are associated with neurodevelopmental diseases, skeletal system abnormalities, anemia, and genitourinary defects. Among the 40 protein-coding genes encompassed within the rearrangement, some have roles in leukocyte biology and immunodeficiency, like SPN and CORO1A. We therefore investigated leukocyte differential counts and disease in 16p11.2 CNV carriers. In our clinically-recruited cohort, we identified three deletion carriers from two families (out of 32 families assessed) with neutropenia and lymphopenia. They had no deleterious single-nucleotide or indel variant in known cytopenia genes, suggesting a possible causative role of the deletion. Noticeably, all three individuals had the lowest copy number of the human-specific BOLA2 duplicon (copy-number range: 3–8). Consistent with the lymphopenia and in contrast with the neutropenia associations, adult deletion carriers from UK biobank (n = 74) showed lower lymphocyte (Padj = 0.04) and increased neutrophil (Padj = 8.31e-05) counts. Mendelian randomization studies pinpointed to reduced CORO1A, KIF22, and BOLA2-SMG1P6 expressions being causative for the lower lymphocyte counts. In conclusion, our data suggest that 16p11.2 deletion, and possibly also the lowest dosage of the BOLA2 duplicon, are associated with low lymphocyte counts. There is a trend between 16p11.2 deletion with lower copy-number of the BOLA2 duplicon and higher susceptibility to moderate neutropenia. Higher numbers of cases are warranted to confirm the association with neutropenia and to resolve the involvement of the deletion coupled with deleterious variants in other genes and/or with the structure and copy number of segments in the CNV breakpoint regions.
Published: 2022

8. A white paper on a neurodevelopmental framework for drug discovery in autism and other neurodevelopmental disorders

Author: Anett Kaale, Tony Charman, Covadonga M. Díaz-Caneja, Claudia Bagni, Matthew W. State, Stefan Leucht, Declan G. Murphy, F. de Andres-Trelles, Spyridon Siafis, Jan K. Buitelaar, Oscar Marín, Emily Simonoff, C. Arango, Daniel Umbricht, J Cusak, Randi J Hagerman, Gahan Pandina, M. Parellada, Sébastien Jacquemont, Eva Loth, P P Wang, and Baltazar Gomez-Mancilla
Subjects: Autism, Psychological intervention, 03 medical and health sciences, 0302 clinical medicine, White paper, Clinical trials, Multidisciplinary approach, 130 000 Cognitive Neurology & Memory, medicine, Genetics, Humans, Pharmacology (medical), Autistic Disorder, Child, Biological Psychiatry, Pharmacology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Drug discovery, Neurodevelopmental disorders, Settore BIO/13, medicine.disease, 030227 psychiatry, ddc, Clinical trial, Neuropsychopharmacology, Psychiatry and Mental health, Neurology, Drug development, Engineering ethics, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: Contains fulltext : 235396.pdf (Publisher’s version ) (Open Access) In the last decade there has been a revolution in terms of genetic findings in neurodevelopmental disorders (NDDs), with many discoveries critical for understanding their aetiology and pathophysiology. Clinical trials in single-gene disorders such as fragile X syndrome highlight the challenges of investigating new drug targets in NDDs. Incorporating a developmental perspective into the process of drug development for NDDs could help to overcome some of the current difficulties in identifying and testing new treatments. This paper provides a summary of the proceedings of the 'New Frontiers Meeting' on neurodevelopmental disorders organised by the European College of Neuropsychopharmacology in conjunction with the Innovative Medicines Initiative-sponsored AIMS-2-TRIALS consortium. It brought together experts in developmental genetics, autism, NDDs, and clinical trials from academia and industry, regulators, patient and family associations, and other stakeholders. The meeting sought to provide a platform for focused communication on scientific insights, challenges, and methodologies that might be applicable to the development of CNS treatments from a neurodevelopmental perspective. Multidisciplinary translational consortia to develop basic and clinical research in parallel could be pivotal to advance knowledge in the field. Although implementation of clinical trials for NDDs in paediatric populations is widely acknowledged as essential, safety concerns should guide each aspect of their design. Industry and academia should join forces to improve knowledge of the biology of brain development, identify the optimal timing of interventions, and translate these findings into new drugs, allowing for the needs of users and families, with support from regulatory agencies.
Published: 2021

9. Sub-diagnostic effects of genetic variants associated with autism

Author: Thomas Rolland, Freddy Cliquet, Richard J.L. Anney, Clara Moreau, Nicolas Traut, Alexandre Mathieu, Guillaume Huguet, Jinjie Duan, Varun Warrier, Swan Portalier, Louise Dry, Claire S. Leblond, Elise Douard, Frédérique Amsellem, Simon Malesys, Anna Maruani, Roberto Toro, Anders D. Børglum, Jakob Grove, Simon Baron-Cohen, Alan Packer, Wendy K. Chung, Sébastien Jacquemont, Richard Delorme, Thomas Bourgeron, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Cardiff University, Centre de Recherches Interdisciplinaires (CRI), Université Paris Cité (UPCité), Université de Montréal (UdeM), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Center for Genomics and Personalized Medicine [Aarhus, Denmark] (CGPM), Department of Biomedicine, Aarhus University, Autism Research Centre [Cambridge, Royaume-Uni], University of Cambridge [UK] (CAM), Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Bioinformatics Research Centre, Aarhus University, Simons Foundation, Columbia University Medical Center (CUMC), Columbia University [New York], This work was funded by Institut Pasteur, the Bettencourt-Schueller Foundation, Université de Paris, the Conny-Maeva Charitable Foundation, the Cognacq Jay Foundation, the Eranet-Neuron (ALTRUISM), the GenMed Labex, AIMS-2-TRIALS which received support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 and the Inception program (Investissement d’Avenir grant ANR-16-CONV-0005). This project has received funding from the European Union’s Horizon 2020 research and innovative program CANDY under grant agreement No 847818., and ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016)
Subjects: Genetics, 0303 health sciences, education.field_of_study, media_common.quotation_subject, Population, Genetic variants, Heterozygote advantage, Biology, medicine.disease, Penetrance, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], mental disorders, medicine, Autism, Psychological resilience, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], education, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, media_common
Abstract: While over a hundred genes are significantly associated with autism, little is known about the prevalence of variants affecting them in the general population. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Using data from more than 13,000 autistic individuals and 210,000 undiagnosed individuals, we provide a gene-level map of the odds ratio for autism associated to rare loss-of-function (LoF) variants in 185 genes robustly associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the phenotype of undiagnosed individuals heterozygous for such variants and show that they exhibit a decrease in fluid intelligence, qualification level and income, and an increase in material deprivation. These effects were larger for LoFs in autism-associated genes than in other LoF-intolerant genes and appeared largely independent of sex and polygenic scores for autism. Using brain imaging data from 21,049 UK-Biobank individuals, we provide evidence for smaller cortical surface area and volume among carriers of LoFs in genes with high odds ratios for autism. Our gene-level map is a key resource to distinguish genes with high and low odds ratio for autism, and highlights the importance of including quantitative data on both diagnosed and undiagnosed individuals to better delineate the effect of genetic variants beyond the categorical diagnosis. Data are available at https://genetrek.pasteur.fr/.
Published: 2022

10. Genotype-phenotype correlation at codon 1740 ofSETD2

Author: Bernt Popp, Shelby Romoser, Lara Menzies, Stacey A. Bélanger, Alireza Radmanesh, Kimberly A. Aldinger, Jennifer Keller-Ramey, Janice Baker, Jane A. Hurst, William B. Dobyns, Schahram Akbarian, Sébastien Jacquemont, Jan Maarten Cobben, Larissa Kerecuk, Kelly Radtke, Joseph T. Shieh, Khadije Jizi, Ian A. Glass, Patrick Watts, Nicola Foulds, Jerica Lenberg, Sumit Punj, George E. Hoganson, Nancy J. Mendelsohn, Rachel Rabin, Ina Sorge, Katarzyna A. Ellsworth, Katharina Löhner, Manuela Siekmeyer, Jennifer Burton, Leah Dowsett, John A. Bernat, Hannah Bombei, John Pappas, Henny H. Lemmink, Francis H. Sansbury, Ingrid M. Wentzensen, Kirsty McWalter, Deborah Osio, Pamela Trapane, Hermine E. Veenstra-Knol, General Paediatrics, Paediatric Genetics, and ANS - Complex Trait Genetics
Subjects: Male, Microcephaly, Mutation, Missense, Biology, Nervous System Malformations, Epigenesis, Genetic, Histone H3, Loss of Function Mutation, Tubulin, SETD2, Intellectual Disability, Genetics, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, histone modification, Epigenetics, AUTISM, Child, Codon, Genetic Association Studies, Genetics (clinical), Loss function, HYPB/SETD2, MARK, IDENTIFICATION, MUTATIONS, METHYLATION, Infant, Histone-Lysine N-Methyltransferase, Methylation, neurodevelopmental, medicine.disease, Histone, genotype phenotype, Neurodevelopmental Disorders, Child, Preschool, biology.protein, Female, clinical genetics
Abstract: The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2.
Published: 2020

11. Lessons Learned From Neuroimaging Studies of Copy Number Variants: A Systematic Review

Author: Borja Rodriguez-Herreros, Ida E Sønderby, Clara A. Moreau, Sandra Martin-Brevet, Bogdan Draganski, Claudia Modenato, Sébastien Jacquemont, Kuldeep Kumar, University of Lausanne (UNIL), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CHU Sainte Justine [Montréal], Université de Montréal (UdeM), Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig] (IMPNSC), Max-Planck-Gesellschaft, Oslo University Hospital [Oslo], University of Oslo (UiO), This work was supported by Calcul Quebec (http://www.calculquebec.ca) and Compute Canada (http://www.computecanada.ca), the Brain Canada Multi-Investigator Initiative, the Canadian Institutes of Health Research (Grant No. CIHR_400528 [to SJ]), the Institute of Data Valorization through the Canada First Research Excellence Fund, and the Healthy Brains for Healthy Lives through the Canada First Research Excellence Fund. SJ is a recipient of a Canada Research Chair in neurodevelopmental disorders and a chair from the Jeanne et Jean Louis Levesque Foundation. CM was supported by a doc.mobility grant provided by the Swiss National Science Foundation. KK was supported by the Institute of Data Valorization Postdoctoral Fellowship program through the Canada First Research Excellence Fund. BD is supported by the Swiss National Science Foundation, Switzerland (NCCR Synapsy, project Grant Nos. 32003B_135679, 32003B_159780, 324730_192755, and CRSK-3_190185) and the Roger De Spoelberch and Leenaards Foundations. IES was supported by the South-Eastern Norway Regional Health Authority (Grant No. 2020060) and received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant No. 847776 (CoMorMent), the Research Council of Norway (Grant No. 223273), and the Kristian Gerhard Jebsen Stiftelsen (Grant No. SKGJ-MED-021)., European Project: 847776,H2020-SC1-2019-Two-Stage-RTD,CoMorMent(2020), Université de Lausanne = University of Lausanne (UNIL), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, DNA Copy Number Variations, Autism Spectrum Disorder, Autism, Structural imaging, Neuroimaging, Biology, Gene dosage, MESH: Magnetic Resonance Imaging, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Humans, Copy-number variation, MESH: Neuroimaging, Biological Psychiatry, Genetics, MESH: Autism Spectrum Disorder, Copy number variants, MESH: Humans, medicine.diagnostic_test, [SCCO.NEUR]Cognitive science/Neuroscience, Brain morphometry, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, MESH: Schizophrenia, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, Schizophrenia, MESH: DNA Copy Number Variations, Psychiatric disorders, 030217 neurology & neurosurgery
Abstract: International audience; Pathogenic copy number variants (CNVs) and aneuploidies alter gene dosage and are associated with neurodevelopmental psychiatric disorders such as autism spectrum disorder and schizophrenia. Brain mechanisms mediating genetic risk for neurodevelopmental psychiatric disorders remain largely unknown, but there is a rapid increase in morphometry studies of CNVs using T1-weighted structural magnetic resonance imaging. Studies have been conducted one mutation at a time, leaving the field with a complex catalog of brain alterations linked to different genomic loci. Our aim was to provide a systematic review of neuroimaging phenotypes across CNVs associated with developmental psychiatric disorders including autism and schizophrenia. We included 76 structural magnetic resonance imaging studies on 20 CNVs at the 15q11.2, 22q11.2, 1q21.1 distal, 16p11.2 distal and proximal, 7q11.23, 15q11-q13, and 22q13.33 (SHANK3) genomic loci as well as aneuploidies of chromosomes X, Y, and 21. Moderate to large effect sizes on global and regional brain morphometry are observed across all genomic loci, which is in line with levels of symptom severity reported for these variants. This is in stark contrast with the much milder neuroimaging effects observed in idiopathic psychiatric disorders. Data also suggest that CNVs have independent effects on global versus regional measures as well as on cortical surface versus thickness. Findings highlight a broad diversity of regional morphometry patterns across genomic loci. This heterogeneity of brain patterns provides insight into the weak effects reported in magnetic resonance imaging studies of cognitive dimension and psychiatric conditions. Neuroimaging studies across many more variants will be required to understand links between gene function and brain morphometry.
Published: 2021

12. Correction

Author: Sébastien Jacquemont, Marianne Bernadette van den Bree, Ffion Evans, Thomas M. Lancaster, Anne M. Maillard, Wendy K. Chung, David Skuse, Jeremy Hall, Jacqueline Smith, Cameron Watson, David Edmund Johannes Linden, Lee Anne Green-Snyder, Nigel Williams, F. Lucy Raymond, Samuel J.R.A. Chawner, Stefanie C. Linden, Michael John Owen, Metamedica, RS: CAPHRI - R6 - Promoting Health & Personalised Care, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, RS: MHeNs - R2 - Mental Health, School for Mental Health and Neuroscienc, and RS: MHeNs - R3 - Neuroscience
Subjects: Adult, Genetics, DNA Copy Number Variations, Correction, Neurosciences. Biological psychiatry. Neuropsychiatry, Biology, Anxiety Disorders, Phenotype, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Neurodevelopmental Disorders, Intellectual Disability, Gene duplication, Humans, Clinical genetics, Chromosome Deletion, Psychiatric disorders, Child, Biological Psychiatry, RC321-571
Abstract: Copy number variants are amongst the most highly penetrant risk factors for psychopathology and neurodevelopmental deficits, but little information about the detailed clinical phenotype associated with particular variants is available. We present the largest study of the microdeletion and -duplication at the distal 1q21 locus, which has been associated with schizophrenia and intellectual disability, in order to investigate the range of psychiatric phenotypes. Clinical and cognitive data from 68 deletion and 55 duplication carriers were analysed with logistic regression analysis to compare frequencies of mental disorders between carrier groups and controls, and linear mixed models to compare quantitative phenotypes. Both children and adults with copy number variants at 1q21 had high frequencies of psychopathology. In the children, neurodevelopmental disorders were most prominent (56% for deletion, 68% for duplication carriers). Adults had increased prevalence of mood (35% for deletion [OR = 6.6 (95% CI: 1.4-40.1)], 55% for duplication carriers [8.3 (1.4-55.5)]) and anxiety disorders (24% [1.8 (0.4-8.4)] and 55% [10.0 (1.9-71.2)]). The adult group, which included mainly genetically affected parents of probands, had an IQ in the normal range. These results confirm high prevalence of neurodevelopmental disorders associated with CNVs at 1q21 but also reveal high prevalence of mood and anxiety disorders in a high-functioning adult group with these CNVs. Because carriers of neurodevelopmental CNVs who show relevant psychopathology but no major cognitive impairment are not currently routinely receiving clinical genetic services widening of genetic testing in psychiatry may be considered.
Published: 2021

13. Stability of Polygenic Scores Across Discovery Genome-Wide Association Studies

Author: Laura Almasy, Kosha Ruparel, Ran Barzilay, David C. Glahn, Sébastien Jacquemont, R.E. Gur, Alison K. Merikangas, and Laura M. Schultz
Subjects: musculoskeletal diseases, Correlation, Genetics, Percentile, Population level, Cohort, Trait, lipids (amino acids, peptides, and proteins), Genome-wide association study, Biology, Stability (probability), Quantile
Abstract: Polygenic scores (PGS) are commonly evaluated in terms of their predictive accuracy at the population level by the proportion of phenotypic variance they explain. To be useful for precision medicine applications, they also need to be evaluated at the individual patient level when phenotypes are not necessarily already known. Hence, we investigated the stability of PGS in European-American (EUR)- and African-American (AFR)-ancestry individuals from the Philadelphia Neurodevelopmental Cohort (PNC) and the Adolescent Brain Cognitive Development (ABCD) cohort using different discovery GWAS for post-traumatic stress disorder (PTSD), type-2 diabetes (T2D), and height. We found that pairs of EUR-ancestry GWAS for the same trait had genetic correlations > 0.92. However, PGS calculated from pairs of sameancestry and different-ancestry GWAS had correlations that ranged from th percentile of PGS overlapping from one height GWAS to another. The degree of overlap decreases sharply as higher quantiles, less heritable traits, and different-ancestry GWAS are considered. PGS computed from different discovery GWAS have only modest correlation at the level of the individual patient, underscoring the need to proceed cautiously with integrating PGS into precision medicine applications.
Published: 2021

14. 11. ANALYSIS OF GENOMIC COPY NUMBER VARIATION AND THEIR INTERACTION WITH POLYGENIC RISK SCORES ACROSS PSYCHIATRIC DISORDERS

Author: Alexander W. Charney, Jonathan Sebat, Jeffrey R. MacDonald, Elise Douard, Stanley Letovsky, Stephen W. Scherer, Omar Shanta, Sébastien Jacquemont, Agathe de Pins, Bhooma Thiruvahindrapuram, Marieke Klein, Oanh Hong, and Jake Humphrey
Subjects: Pharmacology, Genetics, Psychiatry and Mental health, Neurology, Pharmacology (medical), Polygenic risk score, Neurology (clinical), Copy-number variation, Biology, Biological Psychiatry
Published: 2021

15. Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability

Author: Ian J. Deary, Elise Douard, Thomas Renne, Gunter Schumann, Thomas Bourgeron, W. David Hill, Sarah Lippé, Tomáš Paus, Frédérique Tihy, Khadije Jizi, Sarah E. Harris, Myriam Poirier, Nadine Younis, Catherine Schramm, Zdenka Pausova, Zohra Saci, Charles-Olivier Martin, Sébastien Jacquemont, Petra Tamer, Pauline Monin, Sherif Karama, Paul Redmond, Laura Almasy, Gail Davies, Jade England, Maude Auger, Celia M. T. Greenwood, Guillaume Huguet, David J. Porteous, Antoine Main, Géraldine Mathonnet, David C. Glahn, Sabrina Nowak, Emmanuelle Lemyre, Inga Sophia Knoth, Martineau Jean-Louis, Aurélie Labbe, Catalina Maftei, Université de Montréal (UdeM), CHU Sainte Justine [Montréal], Jewish General Hospital, HEC Montréal (HEC Montréal), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), University of Edinburgh, King‘s College London, Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), The Hospital for sick children [Toronto] (SickKids), University of Toronto, McGill University = Université McGill [Montréal, Canada], Douglas Mental Health University Institute [Montréal], Children’s Hospital of Philadelphia (CHOP ), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Hartford Hospital, This research was enabled by support provided by Calcul Quebec and Compute Canada. SJ is a recipient of a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. CS is supported by an Institute for Data Valorization (IVADO) fellowship. PT is supported by a Canadian Institute of Health Research (CIHR) Scholarship Program. GH is supported by the Sainte-Justine Foundation, the Merit Scholarship Program for foreign students, and the Network of Applied Genetic Medicine fellowships. TB is a recipient of a chair of the Bettencourt-Schueler foundation. This work is supported by a grant from the Brain Canada Multi-Investigator initiative and CIHR grant 159734 (SJ, CMTG, TP). The Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada fund the Saguenay Youth Study (SYS). SYS was funded by the Canadian Institutes of Health Research (TP, ZP) and the Heart and Stroke Foundation of Canada (ZP). Funding for the project was provided by the Wellcome Trust. This work was also supported by an NIH award U01 MH119690 granted to LA, SJ, and DG and U01 MH119739., Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, DNA Copy Number Variations, Gene Dosage, Biology, Gene dosage, Genome, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cognition, 0302 clinical medicine, medicine, Humans, genetics, Copy-number variation, Molecular Biology, Gene, Intelligence Tests, Genetics, Intelligence quotient, [SCCO.NEUR]Cognitive science/Neuroscience, Inheritance (genetic algorithm), medicine.disease, Psychiatry and Mental health, psychiatric disorders, 030104 developmental biology, Autism, Haploinsufficiency, 030217 neurology & neurosurgery
Abstract: International audience; Genomic copy number variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well. Here, we identified all CNVs > 50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of intelligence quotient when duplicated or deleted, respectively. Effect sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect size on intelligence occur de novo at the same frequency. We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.
Published: 2021

16. Effect Sizes of Deletions and Duplications on Autism Risk Across the Genome

Author: Clara Moreau, Marie Pier Lord, Aurélie Labbe, Mor Absa Loum, Celia M. T. Greenwood, Mayada Elsabbagh, Laura Almasy, Sébastien Jacquemont, Eva Loth, Catherine Schramm, Laurent Mottron, Borja Rodriguez-Herreros, Guillaume Huguet, Tomas Paus, Petra Tamer, Zdenka Pausova, Zohra Saci, David C. Glahn, Elise Douard, Thomas Bourgeron, Sabrina Nowak, Gunter Schumann, Martineau Jean-Louis, Abderrahim Zeribi, Université de Montréal (UdeM), CHU Sainte Justine [Montréal], Jewish General Hospital, Université de Lausanne (UNIL), King‘s College London, University of Toronto, McGill University = Université McGill [Montréal, Canada], Perelman School of Medicine, University of Pennsylvania [Philadelphia], Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), HEC Montréal (HEC Montréal), Holland Bloorview Kids Rehabilitation Hospital [Toronto, ON, Canada], Centre intégré universitaire de santé et de services sociaux du Nord-de-l'Ile-de-Montréal (CIUSS-NIM), Université de Lausanne = University of Lausanne (UNIL), University of Pennsylvania, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: Male, endocrine system diseases, Autism Spectrum Disorder, Intelligence, Genome, Copy Number Variants, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Gene Duplication, MESH: Child, Copy-number variation, Child, Genetics, MESH: Gene Duplication, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, Psychiatry and Mental health, Autism spectrum disorder, Female, MESH: DNA Copy Number Variations, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, DNA Copy Number Variations, MESH: Autistic Disorder, Biology, behavioral disciplines and activities, Article, 03 medical and health sciences, mental disorders, medicine, Humans, Genetic Predisposition to Disease, MESH: Genome, MESH: Intelligence, Autistic Disorder, MESH: Adolescent, MESH: Humans, [SCCO.NEUR]Cognitive science/Neuroscience, MESH: Adult, medicine.disease, MESH: Male, 030227 psychiatry, IQ, MESH: Gene Deletion, Case-Control Studies, Autism, MESH: Female, Gene Deletion, 030217 neurology & neurosurgery
Abstract: International audience; Objective:Deleterious copy number variants (CNVs) are identified in up to 20% of individuals with autism. However, levels of autism risk conferred by most rare CNVs remain unknown. The authors recently developed statistical models to estimate the effect size on IQ of all CNVs, including undocumented ones. In this study, the authors extended this model to autism susceptibility.Methods:The authors identified CNVs in two autism populations (Simons Simplex Collection and MSSNG) and two unselected populations (IMAGEN and Saguenay Youth Study). Statistical models were used to test nine quantitative variables associated with genes encompassed in CNVs to explain their effects on IQ, autism susceptibility, and behavioral domains.Results:The “probability of being loss-of-function intolerant” (pLI) best explains the effect of CNVs on IQ and autism risk. Deleting 1 point of pLI decreases IQ by 2.6 points in autism and unselected populations. The effect of duplications on IQ is threefold smaller. Autism susceptibility increases when deleting or duplicating any point of pLI. This is true for individuals with high or low IQ and after removing de novo and known recurrent neuropsychiatric CNVs. When CNV effects on IQ are accounted for, autism susceptibility remains mostly unchanged for duplications but decreases for deletions. Model estimates for autism risk overlap with previously published observations. Deletions and duplications differentially affect social communication, behavior, and phonological memory, whereas both equally affect motor skills.Conclusions:Autism risk conferred by duplications is less influenced by IQ compared with deletions. The model applied in this study, trained on CNVs encompassing >4,500 genes, suggests highly polygenic properties of gene dosage with respect to autism risk and IQ loss. These models will help to interpret CNVs identified in the clinic.
Published: 2021

17. Copy-Number Variants in The Contactin-5 Gene Are a Potential Risk Factor for Autism Spectrum Disorder

Author: Elise Douard, Herve Lemaitre, Amélie Musa-Johnson, Lan Xiong, Guy A. Rouleau, Caroline Hayward, Gunter Schumann, Tobias Banaschewski, Boris Chaumette, Sylvane Desrivières, Mor Absa Loum, Guillaume Huguet, Arun L.W. Bokde, Patrick A. Dion, Calwing Liao, Alexandre Dionne-Laporte, Zoe Schmilovich, Qin He, Jay P. Ross, Dan Spiegelman, Sébastien Jacquemont, Martinez Rico, Clara, McGill University = Université McGill [Montréal, Canada], CHU Sainte Justine [Montréal], Centre de Recherche de l’Institut Universitaire en Santé Mentale de Montréal (CRIUSMM), University of Edinburgh, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim], Trinity College Dublin, King‘s College London, Université Paris-Saclay, Montreal Neurological Institute and Hospital, Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: Genetics, genetic structures, neurodevelopment, Potential risk, business.industry, CNTN5, Contactin 5, intronic deletions, CNV, Biology, medicine.disease, behavioral disciplines and activities, ASD, inherited, Text mining, Autism spectrum disorder, mental disorders, medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Copy-number variation, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, Gene
Abstract: BackgroundContactin-5 (CNTN5) is a candidate risk gene for autism spectrum disorder (ASD), yet previous attempts to associate copy-number variants (CNVs) encompassing CNTN5 with ASD-susceptibility were limited by insufficient statistical power. Here, we aim to clarify the putative association between CNTN5 CNVs and ASD-risk using large samples. MethodsFirst, we calculated the prevalence and transmission of CNTN5 CNVs in ASD across three ASD cohorts (SSC, MSSNG, and SPARK), the cases reported in the Mercati et al. study, and the BBGRE database (n = 16,607). Second, we modelled their transmission in children with ASD compared to their unaffected siblings. Third, we assessed their frequency in cases with ASD compared to unselected population controls (n = 24,898) and replicated the findings in UK Biobank (UKBB), an independent general population cohort (n = 459,855). Finally, we evaluated the clinical impact of CNTN5 CNVs by assessing their enrichment in a broad neurodevelopmental disorder (NDD) cohort, and the clinical profile of CNTN5 CNV carriers in the DECIPHER database.ResultsThe prevalence of CNTN5 exonic deletions and duplications was stable across ASD and across unselected cohorts (0.042% and 0.020%, respectively). We found a significant enrichment of intronic CNTN5 deletions CNVs in ASD compared to unselected controls (0.175% and 0.004%, respectively). CNVs in most cases with ASD (29 out of 30, 96.7%) were inherited. Parents transmitted the variants to their affected and unaffected children with the same frequency. No differences in exonic CNTN5 CNVs enrichment between cases with ASD compared to individuals with NDDs was observed. LimitationsThe lack of phenotypic data available for unaffected family members of probands with ASD limits the potential to assess whether CNTN5 CNVs segregate with other neuropsychiatric or sub-threshold autistic traits. Different genotyping or sequencing technologies may affect the differences in CNTN5 CNV prevalence across cohorts.ConclusionCNTN5 CNVs are rare inherited ASD susceptibility variants. They may also confer risk for other neuropsychiatric disorders. We offer a powerful framework to investigate candidate susceptibility variants that may not be detected through small-scale approaches. This approach may reveal more intermediate effect-size variants that are implicated in the etiology of ASD.
Published: 2021

18. Mutations associated with neuropsychiatric conditions delineate functional brain connectivity dimensions contributing to autism and schizophrenia

Author: Carrie E. Bearden, Guillaume Dumas, Aurélie Labbe, Pierre-Olivier Quirion, Stéphane Potvin, Thomas Bourgeron, Clara Moreau, Emmanuel Stip, Kumar Kuldeep, Guillaume Huguet, Amy Lin, Sebastian Urchs, Pierre Bellec, Stéphanie Grot, Alan C. Evans, Catherine Schramm, Sébastien Jacquemont, David Luck, Leila Kushan, Adrianna Mendrek, Pierre Orban, Elise Douard, Université de Montréal (UdeM), Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), McGill University = Université McGill [Montréal, Canada], Centre de Recherche de l’Institut Universitaire en Santé Mentale de Montréal (CRIUSMM), Jewish General Hospital, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), HEC Montréal (HEC Montréal), Semel Institute for Neuroscience and Human Behavior [Los Angeles, Ca], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Bishop’s University [Sherbrooke, Canada], United Arab Emirates University (UAEU), This research was supported by Calcul Quebec and Compute Canada, the Brain Canada Multi investigator research initiative (MIRI), funds from the Institute of Data Valorization (IVADO). S.J. is a recipient of a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. C.S. is supported by a fellowship from the Institute for Data Valorization. Kuldeep Kumar is supported by The Institute of Data Valorization (IVADO) Postdoctoral Fellowship program, through the Canada First Research Excellence Fund. This work was supported by a grant from the Brain Canada Multi-Investigator initiative (S.J.) and a grant from The Canadian Institutes of Health Research (S.J.). Dr P. Bellec is a fellow ('Chercheur boursier Junior 2') of the 'Fonds de recherche du Québec—Santé', Data preprocessing and analyses were supported in part by the Courtois foundation (P.B.)., Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), and University of California-University of California
Subjects: 0301 basic medicine, Male, Autism Spectrum Disorder, Autism, General Physics and Astronomy, MESH: Cognition, MESH: Magnetic Resonance Imaging, Cohort Studies, 0302 clinical medicine, Cognition, Gene Duplication, MESH: Child, 2.1 Biological and endogenous factors, Copy-number variation, Aetiology, Child, lcsh:Science, MESH: Cohort Studies, Pediatric, MESH: Autism Spectrum Disorder, Multidisciplinary, Developmental disorders, MESH: Gene Duplication, Brain, Autism spectrum disorders, Serious Mental Illness, Magnetic Resonance Imaging, Mental Health, Autism spectrum disorder, Schizophrenia, MESH: Young Adult, Child, Preschool, Attention Deficit Disorder (ADD), Female, MESH: DNA Copy Number Variations, Adult, Pediatric Research Initiative, MESH: Mutation, Adolescent, DNA Copy Number Variations, Intellectual and Developmental Disabilities (IDD), Science, Thalamus, MESH: Attention Deficit Disorder with Hyperactivity, Biology, Affect (psychology), behavioral disciplines and activities, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Young Adult, MESH: Brain, Clinical Research, Behavioral and Social Science, mental disorders, Genetics, medicine, Humans, Preschool, MESH: Adolescent, MESH: Humans, [SCCO.NEUR]Cognitive science/Neuroscience, Human Genome, MESH: Child, Preschool, Neurosciences, MESH: Adult, General Chemistry, medicine.disease, MESH: Male, MESH: Schizophrenia, Brain Disorders, 030104 developmental biology, Attention Deficit Disorder with Hyperactivity, MESH: Gene Deletion, Mutation, lcsh:Q, Neuroscience, Insula, MESH: Female, 030217 neurology & neurosurgery, Gene Deletion
Abstract: 16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear. Here we report an analysis of resting-state FC using magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We characterize CNV FC-signatures and use them to identify dimensions contributing to complex idiopathic conditions. CNVs have large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions play a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibit worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms., The impact of neurodevelopmental mutations on functional brain connectivity is poorly understood. Here the authors identify thalamo-sensorimotor dysconnectivity dimensions shared across 16p11.2 and 22q11.2 copy number variants, autism and schizophrenia, but not ADHD.
Published: 2020

19. Insufficient Evidence for 'Autism-Specific' Genes

Author: Kevin J. Mitchell, David T. Miller, John N. Constantino, Wendy K. Chung, Raphael Bernier, Christa Lese Martin, David H. Ledbetter, Thomas Bourgeron, Evan E. Eichler, Thomas D. Challman, Sébastien Jacquemont, Scott M. Myers, Huda Y. Zoghbi, Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), University of Washington [Seattle], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Columbia University Irving Medical Center (CUIMC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Université de Montréal (UdeM), Boston Children's Hospital, Trinity College Dublin, Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, This work was supported, in part, by the National Institute of Mental Health (NIMH) and Eunice Kennedy Shriver National Institute of Child Health and Human Development of the US National Institutes of Health (NIH), under award numbers R01MH074090, R01MH107431, and U01MH11970510 (D.H.L., C.L.M., S.M.M.), Institut Pasteur, Université de Paris, Fondation Bettencourt-Schueller (T.B.), the Simons Foundation Autism Research Initiative (W.K.C.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development award number U54 HD087011 (J.N.C.), NIH grant MH101221 (E.E.E.), and the Canadian Institute of Health Research Canada Research Chair, Canadian Institute of Health Research award number 400528, and NIMH award number U01 MH119690-01 (S.J.). E.E.E. is an investigator of the Howard Hughes Medical Institute. D.T.M. receives an honorarium to serve on the Medical Genetics Committee of the Simons Foundation Powering Autism Research (SPARK) project and receives salary support from NIH grant U41 HG006834 (a Unified Clinical Genomics Database). H.Y.Z. is an investigator of the Howard Hughes Medical Institute., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, Computational biology, MESH: Genotype, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Genetics, medicine, Gene, MESH: Cohort Studies, Genetics (clinical), MESH: Autism Spectrum Disorder, MESH: Humans, MESH: Genetic Testing, Large effect size, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, Phenotype, MESH: Reproducibility of Results, 030104 developmental biology, Autism spectrum disorder, ▪▪▪, Commentary, Autism, Psychology, 030217 neurology & neurosurgery, MESH: Uncertainty
Abstract: International audience; Despite evidence that deleterious variants in the same genes are implicated across multiple neurodevelopmental and neuropsychiatric disorders, there has been considerable interest in identifying genes that, when mutated, confer risk that is largely specific for autism spectrum disorder (ASD). Here, we review the findings and limitations of recent efforts to identify relatively "autism-specific" genes, efforts which focus on rare variants of large effect size that are thought to account for the observed phenotypes. We present a divergent interpretation of published evidence; discuss practical and theoretical issues related to studying the relationships between rare, large-effect deleterious variants and neurodevelopmental phenotypes; and describe potential future directions of this research. We argue that there is currently insufficient evidence to establish meaningful ASD specificity of any genes based on large-effect rare-variant data.
Published: 2020

20. Neuropsychiatric copy number variants exert shared effects on human brain structure

Author: Sandra Martin-Brevet, Kuldeep Kumar, Clara Moreau, M. Mallar Chakravarty, Florence Deguire, Elise Douard, Guillaume Huguet, Sarah Lippé, Carrie E. Bearden, Sébastien Jacquemont, Fanny Thébault-Dagher, Claudia Modenato, Sonia Richetin, Charlebois A, Danilo Bzdok, Côté, Bogdan Draganski, Aurélie Pain, Lester Melie-Garcia, van den Bree Mb, Ana I. Silva, Jean-Louis Martineau, Nadine Younis, Petra Tamer, Anne M. Maillard, Charles-Olivier Martin, Jeremy Hall, Michael John Owen, Leila Kushan, David E. J. Linden, Catherine Schramm, and Borja Rodriguez-Herreros
Subjects: Genetics, 0303 health sciences, Mutation, Brain morphometry, Human brain, Biology, medicine.disease, medicine.disease_cause, 03 medical and health sciences, Brain anatomy, 0302 clinical medicine, medicine.anatomical_structure, Neuroimaging, Schizophrenia, mental disorders, medicine, Autism, Copy-number variation, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: BackgroundCopy Number Variants (CNVs) associated with autism and schizophrenia have large effects on brain anatomy. Yet, neuroimaging studies have been conducted one mutation at a time. We hypothesize that neuropsychiatric CNVs may exert general effects on brain morphometry because they confer risk for overlapping psychiatric conditions.MethodsWe analyzed T1-weighted MRIs and characterized shared patterns on brain anatomy across 8 neuropsychiatric CNVs. Clinically ascertained samples included 1q21.1 (n=48), 16p11.2 (n=156), or 22q11.2 (n=96) and 331 non-carriers. Non-clinically ascertained samples from the UK Biobank included 1q21.1 (n=19), 16p11.2 (n=8), 22q11.2 (n=9), 15q11.2 (n=148) and 965 non-carriers. Canonical correlation analysis (CCA) and univariate models were used to interrogate brain morphometry changes across 8 CNVs.ResultsEight CNVs affect regional brain volumes along two main gene-morphometry dimensions identified by CCA. While fronto-temporal regions contributed to dimension 1, dimension 2 was driven by subcortical, parietal and occipital regions. Consistently, voxel-wise whole-brain analyses identified the same regions involved in patterns of alteration present across the 4 deletions and duplications. These neuroanatomical patterns are similar to those observed in cross-psychiatric disorder meta-analyses. Deletions and duplications at all 4 loci show mirror effects at either the global and/or the regional level.ConclusionNeuropsychiatric CNVs share neuroanatomical signatures characterized by a parsimonious set of brain dimensions. The latter may underlie the risk conferred by CNVs for a similar spectrum of neuropsychiatric conditions.
Published: 2020

21. Genome wide analysis of gene dosage in 24,092 individuals shows that 10,000 genes modulate cognitive ability

Author: Guillaume Huguet, Catherine Schramm, Elise Douard, Tamer Petra, Antoine Main, Pauline Monin, Jade England, Khadije Jizi, Thomas Renne, Myriam Poirier, Sabrina Nowak, Charles-Olivier Martin, Nadine Younis, Inga Sophia Knoth, Martineau Jean-Louis, Zohra Saci, Maude Auger, Frédérique Tihy, Géraldine Mathonnet, Catalina Maftei, France Léveillé, David Porteous, Gail Davies, Paul Redmond, Sarah E. Harris, W. David Hill, Emmanuelle Lemyre, Gunter Schumann, Thomas Bourgeron, Zdenka Pausova, Tomas Paus, Sherif Karama, Sarah Lippe, Ian J. Deary, Laura Almasy, Aurélie Labbe, David Glahn, Celia M.T. Greenwood, and Sébastien Jacquemont
Subjects: Genetics, Regulation of gene expression, 0303 health sciences, Inheritance (genetic algorithm), Biology, medicine.disease, Gene dosage, Genome, 03 medical and health sciences, 0302 clinical medicine, medicine, Autism, Copy-number variation, Haploinsufficiency, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Genomic Copy Number Variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect-size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect-sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well.Here, we identified all CNVs >50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect-size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of IQ when duplicated or deleted, respectively. Effect-sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect-sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect-size on intelligence occur de novo at the same frequency.We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect-sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.
Published: 2020

22. The general impact of haploinsufficiency on brain connectivity underlies the pleiotropic effect of neuropsychiatric CNVs

Author: Claudia Modenato, Amy Lin, Sarah Lippé, Carrie E. Bearden, Aurélie Labbe, David Edmund Johannes Linden, Marianne Bernadette van den Bree, Jean-Louis Martineau, Nadine Younis, Pierre Bellec, Petra Tamer, Sebastian Urchs, Hanad Sharmarke, Aia E. Jønch, Elise Douard, Khadije Jizi, Sandra Martin-Brevet, Clara Moreau, Jeremy Hall, Anne M. Maillard, Sébastien Jacquemont, Charles-Olivier Martin, Celia M. T. Greenwood, Guillaume Huguet, Pierre Orban, Kumar Kuldeep, Paul M. Thompson, Michael John Owen, and Ana I. Silva
Subjects: Genetics, 0303 health sciences, congenital, hereditary, and neonatal diseases and abnormalities, endocrine system diseases, Cognition, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, Schizophrenia, Basal ganglia, mental disorders, medicine, Autism, Attention deficit hyperactivity disorder, Copy-number variation, Haploinsufficiency, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Large effect-size mutations such as copy number variants (CNVs) have the potential to provide key insights into the underlying biological mechanisms linking deleterious genetic variants to brain architecture and neuropsychiatric disorders. To date, the effect of CNVs on functional brain connectivity remains mostly unstudied, and findings are derived from analyses conducted one mutation at a time. The lack of systematic cross-CNV comparisons hinders our understanding of any potential general mechanisms linking CNVs to effects on brain organization. We performed connectome-wide analyses using resting-state functional MRI data from 436 carriers of neuropsychiatric CNVs at the 1q21.1, 15q11.2, 16p11.2, 22q11.2 loci, and 4 neutral-effect CNVs, 66 carriers of scarcer neuropsychiatric CNVs, 756 individuals with idiopathic autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder, and 5,377 controls. Neuropsychiatric CNVs showed global shifts of mean connectivity. The effect size of CNVs on relative connectivity (adjusted for the mean) was correlated with the known level of neuropsychiatric risk conferred by CNVs. We reported architecture similarities between individuals with idiopathic psychiatric conditions and high-risk neuropsychiatric-CNVs, predominantly in the thalamus, the posterior cingulate cortex, and the anterior insula. We identified a linear relationship between connectivity and intolerance to haploinsufficiency measured for all genes encompassed by CNVs across 18 loci. This profile involved the thalamus, the basal ganglia, somatomotor and frontoparietal networks and was correlated with lower general intelligence and higher autism severity scores. An exploratory factor analysis confirmed the contribution of these regions to three latent components shared across CNVs and neuropsychiatric disorders. We posit that deleting genes intolerant to haploinsufficiency reorganize connectivity along general dimensions irrespective of where deletions occur in the genome. This haploinsufficiency brain signature opens new avenues to understand polygenicity in psychiatric conditions and the pleiotropic effect of CNVs on cognition and risk for neuropsychiatric disorders.
Published: 2020
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23. Effects-sizes of deletions and duplications on autism risk across the genome

Author: Elise Douard, Sébastien Jacquemont, Clara Moreau, Martineau Jean-Louis, David C. Glahn, Celia M. T. Greenwood, Guillaume Huguet, Mayada Elsabbagh, Tomáš Paus, Gunter Schumann, Zdenka Pausova, Marie-Pier Lord, Aurélie Labbe, Catherine Schramm, Mor Absa Loum, Borja Rodriguez-Herreros, Abderrahim Zeribi, Laurent Mottron, Zohra Saci, Thomas Bourgeron, Laura Almasy, Eva Loth, Sabrina Nowak, and Petra Tamer
Subjects: Genetics, 0303 health sciences, Intelligence quotient, Cognition, Biology, medicine.disease, Affect (psychology), Gene dosage, Genome, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Autism, Copy-number variation, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: ObjectiveDeleterious copy number variants (CNVs) are identified in up to 20% of individuals with autism. However, only 13 genomic loci have been formally associated with autism because the majority of CNVs are too rare to perform individual association studies. To investigate the implication of undocumented CNVs in neurodevelopmental disorders, we recently developed a new framework to estimate their effect-size on intelligence quotient (IQ) and sought to extend this approach to autism susceptibility and multiple cognitive domains.MethodsWe identified CNVs in two autism samples (Simons Simplex Collection and MSSNG) and two unselected populations (IMAGEN and Saguenay Youth Study). Statistical models integrating scores of genes encompassed in CNVs were used to explain their effect on autism susceptibility and multiple cognitive domains.ResultsAmong 9 scores of genes, the “probability-of-being loss-of-function intolerant” (pLI) best explains the effect of CNVs on IQ and autism risk. Deletions decrease IQ by a mean of 2.6 points per point of pLI. The effect of duplications on IQ is three-fold smaller. The odd ratios for autism increases when deleting or duplicating any point of pLI. This increased autism risk is similar in subgroups of individuals below or above median IQ. Once CNV effects on IQ are accounted for, autism susceptibility remains mostly unchanged for duplications but decreases for deletions. Model estimates for autism risk overlap with previously published observations. Deletions and duplications differentially affect social communication, behaviour, and phonological memory, whereas both equally affect motor skills.ConclusionsAutism risk conferred by duplications is less influenced by IQ compared to deletions. CNVs increase autism risk similarly in individuals with high and low IQ. Our model, trained on CNVs encompassing >4,500 genes, suggests highly polygenic properties of gene dosage with respect to autism risk. These models will help interpreting CNVs identified in the clinic.
Published: 2020
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24. A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants

Author: Sarah Curran, LeeAnne Green-Snyder, Caitlin C. Clements, Hayley Moss, Jacob A. S. Vorstman, Joanne L. Doherty, Sébastien Jacquemont, Louise Gallagher, Wendy R. Kates, Robin P. Goin-Kochel, Raphael Bernier, Ellen Hanson, Marina Mihaljevic, Wendy K. Chung, A. Maillard, Samuel J.R.A. Chawner, Tara L. Wenger, Kevin M. Antshel, Donna M. McDonald-McGinn, Raquel E. Gur, Carrie E. Bearden, Michael John Owen, Milica Pejovic-Milovancevic, Judith Miller, Richard Anney, Robert T. Schultz, Ania M Fiksinski, Leila Kushan, Marianne Bernadette van den Bree, Goran Cuturilo, and Jeremy Hall
Subjects: Genetics, 0303 health sciences, Intelligence quotient, business.industry, Genetic variants, medicine.disease, Phenotype, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Gene duplication, medicine, Trait, Etiology, Autism, Copy-number variation, business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: ObjectiveCertain copy number variants (CNVs) greatly increase risk of autism. We conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships.MethodsThis international study included 547 individuals (12.3 years (SD=4.2), 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers and 45 22q11.2 duplication carriers), as well as 2027 individuals (9.1 years (SD=4.9), 86% male) with autism of heterogeneous aetiology. The Autism Diagnostic Interview-Revised (ADI-R) and IQ testing were conducted.ResultsThe four genetic variant groups differed in autism severity, autism subdomain profile as well as IQ profile. However, we found substantial variability in phenotypic outcome within individual genetic variant groups (74% to 97% of the variance depending on the trait), whereas variability between groups was low (1% to 21% depending on trait). We compared CNV carriers who met autism criteria, to individuals with heterogeneous autism, and a range of profile differences were identified. Using clinical cut-offs, we found that 54% of individuals with one of the 4 CNVs who did not meet full autism diagnostic criteria nonetheless had elevated levels of autistic traits.ConclusionMany CNV carriers do not meet full diagnostic criteria for autism, but nevertheless meet clinical cut-offs for autistic traits. Although we find profile differences between variants, there is considerable variability in clinical symptoms within the same variant.
Published: 2020

25. Developmental trajectories of neuroanatomical alterations associated with the 16p11.2 Copy Number Variations

Author: Alonso, Cárdenas-de-la-Parra, Sandra, Martin-Brevet, Clara, Moreau, Borja, Rodriguez-Herreros, Vladimir, S Fonov, Anne, M Maillard, Nicole, R Zürcher, 2 European Consortium, 16p11., Nouchine Hadjikhani 48, Jacques, S Beckmann 49, Alexandre Reymond 50, Bogdan Draganski 51, Sébastien Jacquemont 52, D Louis Collins 1, Marie-Claude Addor, 7, Joris Andrieux, 8, Benoît Arveiler, 9, Geneviève Baujatm 10, Frédérique Sloan-Bénan 11, Marco, Belfiore, Dominique Bonneau 12, Sonia Bouquillon 13, Odile Boute 14, Brusco, Alfredo, Tiffany Busa 16, Jean-Hubert Caberg 17, Dominique Campion 18, Vanessa Colombert 19, Marie-Pierre Cordier 20, Albert David 21, François-Guillaume Debray 22, Marie-Ange Delrue 23, Martine Doco-Fenzy 24, Ulrike Dunkhase-Heinl 25, Patrick Edery 20, Christina Fagerberg 26, Laurence Faivre 27, Francesca, Forzano, David Genevieve 29, Marion Gérard 30, Giachino, Daniela Francesca, Agnès Guichet 32, Olivier Guillin 33, Delphine Héron 34, Bertrand Isidor 21, Aurélia Jacquette 34, Sylvie Jaillard 35, Hubert Journel 19, Boris Keren 36, Didier Lacombe, 9, Sébastien Lebon 37, Cédric Le Caignec 38, Marie-Pierre Lemaître 39, James Lespinasse 40, Michèle Mathieu-Dramart 41, Sandra Mercier 21, Cyril Mignot 34, Chantal Missirian 16, Florence Petit 42, Kristina Pilekær Sørensen 26, Lucile Pinson 29, Ghislaine Plessis 30, Fabienne Prieur 43, Caroline Rooryck-Thambo 44, Rossi, Massimiliano, Damien Sanlaville 45, Britta Schlott Kristiansen 26, Caroline Schluth-Bolard 45, Marianne Till 20, Mieke Van Haelst 46, Lionel Van Maldergem, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), McConnell Brain Imaging Centre (MNI), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Ecophysiologie Végétale, Agronomie et Nutritions (EVA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Recherche Agronomique (INRA), Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Human Genetics, Université de Lausanne (UNIL), Service de génétique médicale, Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, EHESP-Irset (EHESP-Irset), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], National Institute of Child Health and Human Development, National Institute on Drug Abuse, 3388, MIRI Brain Canada, 201803PJT 400528 BSB, IVADO fund: a Canadian Institute of Health Research, Fonds de Recherche Nature et technologies du Québec, Roger De Spoelberch, Partridge Foundations, National Institute of Mental Health, N01-MH9-0002, National Institute of Neurological Disorders and Stroke, 33CS30-148401, National Science Foundation, MOP-111169, Canadian Institutes of Health Research, 31003A_160203, Schweizerischer Nationalfonds zur F&#x00F6, rderung der Wissenschaftlichen Forschung, Horizon 2020, Fondation Leenaards, and McGill University-McGill University
Subjects: Adult, Adolescent, DNA Copy Number Variations, Cognitive Neuroscience, Biology, computer.software_genre, 050105 experimental psychology, Imaging, White matter, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, Voxel, Chromosome Duplication, Gene duplication, medicine, Genetics, Humans, 0501 psychology and cognitive sciences, Copy-number variation, Child, ComputingMilieux_MISCELLANEOUS, 16p11.2 Copy number variants, Brain development, Neurodevelopmental disorders, Normative growth trajectories, [SCCO.NEUR]Cognitive science/Neuroscience, 05 social sciences, Brain, medicine.anatomical_structure, Neurology, Evolutionary biology, Child, Preschool, Endophenotype, Human genome, Chromosome Deletion, Insula, computer, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery
Abstract: Most of human genome is present in two copies (maternal and paternal). However, segments of the genome can be deleted or duplicated, and many of these genomic variations (known as Copy Number Variants) are associated with psychiatric disorders. 16p11.2 copy number variants (breakpoint 4–5) confer high risk for neurodevelopmental disorders and are associated with structural brain alterations of large effect-size. Methods used in previous studies were unable to investigate the onset of these alterations and whether they evolve with age. In this study, we aim at characterizing age-related effects of 16p11.2 copy number variants by analyzing a group with a broad age range including younger individuals. A large normative developmental dataset was used to accurately adjust for effects of age. We normalized volumes of segmented brain regions as well as volumes of each voxel defined by tensor-based morphometry. Results show that the total intracranial volumes, the global gray and white matter volumes are respectively higher and lower in deletion and duplication carriers compared to control subjects at 4.5 years of age. These differences remain stable through childhood, adolescence and adulthood until 23 years of age (range: 0.5 to 1.0 Z-score). Voxel-based results are consistent with previous findings in 16p11.2 copy number variant carriers, including increased volume in the calcarine cortex and insula in deletions, compared to controls, with an inverse effect in duplication carriers (1.0 Z-score). All large effect-size voxel-based differences are present at 4.5 years and seem to remain stable until the age of 23. Our results highlight the stability of a neuroimaging endophenotype over 2 decades during which neurodevelopmental symptoms evolve at a rapid pace.
Published: 2019

26. Protein synthesis levels are increased in a subset of individuals with fragile X syndrome

Author: Giulia Cencelli, Giorgia Pedini, Laura Pacini, Yunsheng He, Rob Willemsen, Laura D'Andrea, Fabrizio Gasparini, Randi J Hagerman, Baltazar Gomez-Mancilla, Marwa Eldeeb, Izabela Rozenberg, Claudia Bagni, Flora Tassone, Sébastien Jacquemont, Aia E. Jønch, and Clinical Genetics
Subjects: 0301 basic medicine, Male, Fragile X Mental Retardation Protein/biosynthesis, Autism Spectrum Disorder, Autism, Neurons/metabolism, Disease, Hippocampus, Medical and Health Sciences, Fragile X Mental Retardation Protein, Mice, Intellectual disability, Adolescent, Adult, Aged, Animals, Autism Spectrum Disorder/genetics, Autism Spectrum Disorder/physiopathology, Child, Disease Models, Animal, Female, Fibroblasts/metabolism, Fibroblasts/pathology, Fragile X Mental Retardation Protein/genetics, Fragile X Syndrome/genetics, Fragile X Syndrome/physiopathology, Hippocampus/metabolism, Hippocampus/physiopathology, Humans, Mice, Knockout, Middle Aged, Neurons/pathology, Young Adult, Protein biosynthesis, 2.1 Biological and endogenous factors, Aetiology, Genetics (clinical), Pediatric, Genetics, Neurons, Genetics & Heredity, Settore BIO/13, General Medicine, Articles, Biological Sciences, Fragile X syndrome, Mental Health, Autism spectrum disorder, Biomarker (medicine), Corrigendum, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Intellectual and Developmental Disabilities (IDD), Knockout, Biology, 03 medical and health sciences, Rare Diseases, Downregulation and upregulation, Internal medicine, medicine, Molecular Biology, Animal, Neurosciences, Fibroblasts, medicine.disease, FMR1, Fragile X Syndrome, Brain Disorders, Endocrinology, 030104 developmental biology, Disease Models
Abstract: Fragile X syndrome (FXS) is a monogenic form of intellectual disability and autism spectrum disorder caused by the absence of the fragile X mental retardation protein (FMRP). In biological models for the disease, this leads to upregulated mRNA translation and as a consequence, deficits in synaptic architecture and plasticity. Preclinical studies revealed that pharmacological interventions restore those deficits, which are thought to mediate the FXS cognitive and behavioral symptoms. Here, we characterized the de novo rate of protein synthesis in patients with FXS and their relationship with clinical severity. We measured the rate of protein synthesis in fibroblasts derived from 32 individuals with FXS and from 17 controls as well as in fibroblasts and primary neurons of 27 Fmr1 KO mice and 20 controls. Here, we show that levels of protein synthesis are increased in fibroblasts of individuals with FXS and Fmr1 KO mice. However, this cellular phenotype displays a broad distribution and a proportion of fragile X individuals and Fmr1 KO mice do not show increased levels of protein synthesis, having measures in the normal range. Because the same Fmr1 KO animal measures in fibroblasts predict those in neurons we suggest the validity of this peripheral biomarker. Our study offers a potential explanation for the comprehensive drug development program undertaken thus far yielding negative results and suggests that a significant proportion, but not all individuals with FXS, may benefit from the reduction of excessive levels of protein synthesis.
Published: 2018

27. Analysis of Genomic Copy Number Variation Across Psychiatric Disorders

Author: Oanh Hong, Jake Humphrey, Agathe de Pins, Elise Douard, Zohra Saci, Jeffrey R. MacDonald, Marieke Klein, Stan Stan Letovsky, Stephen W. Scherer, Omar Shanta, Sébastien Jacquemont, Alexander W. Charney, Bhooma Thiruvahindrapuram, and Jonathan Sebat
Subjects: Genetics, Copy-number variation, Biology, Biological Psychiatry
Published: 2021

28. Estimating the effect size of the 15Q11.2 BP1–BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice

Author: Jacques Puechberty, Charlotte Brasch-Andersen, Aurélie Pain, Sonia Richetin, Sébastien Jacquemont, Usha Kini, Anke Van Dijck, Christiane Zweier, Elise Douard, Lilian Bomme Ousager, Aia E. Jønch, Cédric Le Caignec, Anders Bojesen, Bertrand Isidor, Damien Sanlaville, Carolyn Campbell, James Lespinasse, Anne-Bine Skytte, Henrietta Lefroy, Helle Hjalgrim, Marie Ange Delrue, Marzia Passeggeri, Clara Moreau, Emmanuelle Lemyre, Rikke S. Møller, R. Frank Kooy, Jean-Hubert Caberg, David Geneviève, University of Southern Denmark (SDU), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Antwerp University Hospital [Edegem] (UZA), Service of Neurology [CHUV, Lausanne, Switzerland], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Oxford University Hospitals NHS Trust, University of Oxford [Oxford], Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, 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)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Métropole Savoie [Chambéry], Aarhus University Hospital, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Centre Hospitalier Universitaire de Liège (CHU-Liège), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark], and 15q11.2 Working Group
Subjects: Male, Pediatrics, Heart malformation, 15q11.2 copy-number variants, [SDV]Life Sciences [q-bio], Neurodevelopmental Disorders/genetics, Epilepsy/genetics, Cohort Studies, Epilepsy, 0302 clinical medicine, Loss of Function Mutation, Gene duplication, Genetics (clinical), Sequence Deletion, 0303 health sciences, loss-of-function intolerance, neurodevelopmental disorders, Microdeletion syndrome, congenital heart disease, Schizophrenia, Female, Autistic Disorder/genetics, medicine.medical_specialty, Heart Diseases, DNA Copy Number Variations, Genetic counseling, 03 medical and health sciences, Intellectual Disability, Genetics, medicine, Humans, Autistic Disorder, Biology, 030304 developmental biology, Heart Diseases/congenital, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, Intellectual Disability/genetics, Case-Control Studies, Autism, epilepsy, Clinical case, Human medicine, Copy-Number Variation, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: BackgroundThe 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case–control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders.MethodsWe performed meta-analyses on new and previously published case–control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers. 15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant.ResultsThe deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias.ConclusionsWe recommend that the deletion should be classified as ‘pathogenic of mild effect size’. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting.
Published: 2019

29. Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

Author: Bogdan Draganski, Thomas Arbogast, Alexandre Reymond, Sébastien Jacquemont, Anna Pellaz, R. Mark Henkelman, Herta Ademi, Erica E. Davis, Yann Herault, Jacob Ellegood, Katrin Männik, Triin Laisk, Sandra Martin-Brevet, Maarja Lepamets, Jacqueline Chrast, Jean-Christophe Stehle, Nicholas Katsanis, Lily R. Qiu, Samuel Rotman, Jason P. Lerch, Andrea Messina, Kaido Lepik, Serge Nef, Zoltán Kutalik, Estelle Dubruc, Cecilia M. Lindgren, Reedik Mägi, Catia Attanasio, Zachary A. Kupchinsky, and Hedi Peterson
Subjects: GnRH Neuron, Genetics, 0303 health sciences, 030305 genetics & heredity, Genome-wide association study, Locus (genetics), Disease, Biology, Phenotype, 03 medical and health sciences, Mendelian randomization, Gene, 030304 developmental biology, Genetic association
Abstract: Whereas genome-wide association studies (GWAS) allowed identifying thousands of associations between variants and traits, their success rate in pinpointing causal genes has been disproportionately low. Here, we integrate biobank-scale phenotype data from carriers of a rare copy-number variant (CNV), Mendelian randomization and animal modeling to identify causative genes in a GWAS locus for age at menarche (AaM). We show that the dosage of the 16p11.2 BP4-BP5 interval is correlated positively with AaM in the UK and Estonian biobanks and 16p11.2 clinical cohorts, with a directionally consistent trend for pubertal onset in males. These correlations parallel an increase in reproductive tract disorders in both sexes. In support of these observations, 16p11.2 mouse models display perturbed pubertal onset and structurally altered reproductive organs that track with CNV dose. Further, we report a negative correlation between the 16p11.2 dosage and relative hypothalamic volume in both humans and mice, intimating a perturbation in the gonadotropin-releasing hormone (GnRH) axis. Two independent lines of evidence identified candidate causal genes for AaM; Mendelian randomization and agnostic dosage modulation of each 16p11.2 gene in zebrafish gnrh3:egfp models. ASPHD1, expressed predominantly in brain and pituitary gland, emerged as a major phenotype driver; and it is subject to modulation by KCTD13 to exacerbate GnRH neuron phenotype. Together, our data highlight the power of an interdisciplinary approach to elucidate disease etiologies underlying complex traits.
Published: 2019

30. Duplication of 10q24 locus: broadening the clinical and radiological spectrum

Author: Joris Andrieux, Anna Sowińska-Seidler, Joo Wook Ahn, Elena Pollina, Clarisse Baumann, Chantal Farra, Florence Petit, Sébastien Jacquemont, Muriel Holder-Espinasse, Philippe Jonveaux, Jane A. Hurst, Sylvie Manouvrier-Hanu, Magdalena Socha, Neeti Ghali, Sahar Mansour, Albert David, Anne-Sylvie Valat, Michèle Mathieu-Dramard, Anne Moncla, Annick Toutain, Alain Verloes, Anna Jakubiuk-Tomaszuk, Nayana Lahiri, Estelle Colin, Annick Rossi, David Zhang, Philippe Bourgeot, Aleksander Jamsheer, Fabienne Escande, Marion Gérard, Aurélie Mezel, Valérie Cormier-Daire, Ghislaine Plessis, Christine Patch, Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), biology and pathological laboratory, Institut de Génétique Médicale [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Jeanne de Flandre [Lille], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Agricultural University of Krakow, Université de Lorraine (UL), Service de génétique médicale, CHU Amiens-Picardie, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, MLab, Dauphine Recherches en Management (DRM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Inst MitoVasc, Equipe MitoLab, Université d'Angers (UA), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Wessex Clinical Genetics Service, Wessex clinical genetics service, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Laboratoire de Génétique Chromosomique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Department of Clinical Genetics/EMGO Institute for Health and Care research, Biometrics Research Center, The Hong Kong Polytechnic University [Hong Kong] (POLYU), Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), 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 de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: Adult, Male, Proteasome Endopeptidase Complex, BTRC, Limb Deformities, Congenital, Locus (genetics), Review Article, Biology, Young Adult, 03 medical and health sciences, Exon, Segmental Duplications, Genomic, Proto-Oncogene Proteins, Gene duplication, Genetics, Humans, Genetic Predisposition to Disease, Genetics (clinical), Segmental duplication, Gene Rearrangement, Regulation of gene expression, Comparative Genomic Hybridization, 0303 health sciences, Chromosomes, Human, Pair 10, F-Box Proteins, 030305 genetics & heredity, Infant, Penetrance, Pedigree, Radiography, Wnt Proteins, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Female, Hand Deformities, Congenital, Limb morphogenesis
Abstract: International audience; Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.
Published: 2019

31. Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita

Author: Merryn V. E. Macville, David Hunt, Richard Webster, Suzanna G.M. Frints, Alberto Fernández-Jaén, Shelagh Joss, Andrew G. L. Douglas, Margje Sinnema, Lesley M McGregor, Vera M. Kalscheuer, Abhijit Dixit, Paulien A. Terhal, Arthur Lee, Sébastien Jacquemont, Omar A. Abdul-Rahman, Peter Wieacker, Koen L.I. van Gassen, Norbert Utzig, Marcus Lee, Vanessa Suckow, Gunnar Houge, Danita Velasco, Cheryl Longman, Holly H. Zimmerman, Elizabeth C. Engle, Bryce A. Mendelsohn, Salwan Al-Nasiry, Suzanne M. Koudijs, Saskia M. Maas, Diana Baralle, Hiromi Hirata, Kees E. P. van Roozendaal, Servi J. C. Stevens, Raoul C.M. Hennekam, Roberto Colombo, Ulrike Kordaß, Gyri Aasland Gradek, Friederike Hennig, APH - Quality of Care, Human Genetics, Amsterdam Neuroscience - Complex Trait Genetics, MUMC+: DA KG Bedrijfsbureau (9), Klinische Genetica, MUMC+: DA KG Polikliniek (9), MUMC+: DA KG Lab Centraal Lab (9), Obstetrie & Gynaecologie, MUMC+: MA Medische Staf Obstetrie Gynaecologie (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: MA Med Staf Spec Neurologie (9)
Subjects: Male, INTELLECTUAL DISABILITY, Enfermedad del sistema nervioso, CONTRACTURES, Pie zambo, Genes, X-Linked, Missense mutation, Genetics(clinical), Frameshift Mutation, EXCHANGE, Zebrafish, Genetics (clinical), Sequence Deletion, media_common, Arthrogryposis, Genetics, Sex Characteristics, Paraplejía, medicine.diagnostic_test, 2 microdeletion, Intracellular Signaling Peptides and Proteins, complicated spastic paraplegia/ spasticity, METHYLATION, Espasticidad muscular, Nuclear Proteins, spasticity, Phenotype, Pedigree, Codon, Nonsense, akinesia, Female, Neurogenic arthrogryposis multiplex congenita, media_common.quotation_subject, fetal hypo, Nonsense, Mutation, Missense, Biology, DIAGNOSIS, Article, Frameshift mutation, medicine, Animals, Humans, Genetic Predisposition to Disease, Gene, Genetic testing, ZC4H2-Associated Rare Disorders (ZARD), SPECTRUM, Arthrogryposis multiplex congenita, MUTATIONS, fetal hypo-/akinesia, feet, club foot/-feet, ZC4H2, GENE, Genética, DELETIONS, Disease Models, Animal, complicated spastic paraplegia, Mutation, Xq11.2 microdeletion, Xq11, MENTAL-RETARDATION, club foot
Abstract: Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/or (neurogenic) AMC. Sin financiación 4.124 JCR (2019) Q1, 45/178 Genetics & Heredity 2.410 SJR (2019) Q1, 43/356 Genetics No data IDR 2019 UEM
Published: 2019

32. The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Author: Maria Nicla Loviglio, Thomas Arbogast, Aia Elise Jønch, Stephan C. Collins, Konstantin Popadin, Camille S. Bonnet, Giuliana Giannuzzi, Anne M. Maillard, Sébastien Jacquemont, Binnaz Yalcin, Nicholas Katsanis, Christelle Golzio, Alexandre Reymond, Christina Fagerberg, Charlotte Brasch Andersen, Martine Doco-Fenzy, Marie-Ange Delrue, Laurence Faivre, Benoit Arveiler, David Geneviève, Anouck Schneider, Marion Gerard, Joris Andrieux, Salima El Chehadeh, Elise Schaefer, Christel Depienne, Mieke Van Haelst, Eva H. Brilstra, Ellen Van Binsbergen, Jeske van Harssel, Lars T. van der Veken, James F. Gusella, Yiping Shen, Elyse Mitchell, Usha Kini, Lara Hawkes, Carolyn Campbell, Florence Niel Butschi, Marie-Claude Addor, Jacques S. Beckmann, Université de Lausanne = University of Lausanne (UNIL), Duke University [Durham], Lausanne University Hospital, Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immanuel Kant Baltic Federal University (IKBFU), 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), 16p11.2 Consortium: Maria Nicla Loviglio, Aia Elise Jønch, Konstantin Popadin, Giuliana Giannuzzi, Anne M Maillard, Christina Fagerberg, Charlotte Brasch Andersen, Martine Doco-Fenzy, Marie-Ange Delrue, Laurence Faivre, Benoit Arveiler, David Geneviève, Anouck Schneider, Marion Gerard, Joris Andrieux, Salima El Chehadeh, Elise Schaefer, Christel Depienne, Mieke Van Haelst, Eva H Brilstra, Ellen Van Binsbergen, Jeske van Harssel, Lars T van der Veken, James F Gusella, Yiping Shen, Elyse Mitchell, Usha Kini, Lara Hawkes, Carolyn Campbell, Florence Niel Butschi, Marie-Claude Addor, Jacques S Beckmann, Sébastien Jacquemont, Alexandre Reymond., Dupuis, Christine, Amsterdam Reproduction & Development (AR&D), Human genetics, and Amsterdam Neuroscience - Complex Trait Genetics
Subjects: Male, 0301 basic medicine, epistasis, Microcephaly, obesity, Embryo, Nonmammalian, Phosphoproteins/physiology, MAPK3, [SDV]Life Sciences [q-bio], Chromosome Disorders, Adaptor Proteins, Signal Transducing/genetics, zebrafish, Cohort Studies, Microcephaly/genetics, Mice, 0302 clinical medicine, Chromosome Disorders/genetics, Gene duplication, Genetics(clinical), Child, Zebrafish, Genetics (clinical), Aged, 80 and over, Mice, Knockout, Genetics, ZAP70, Brain, Gene Expression Regulation, Developmental, head size, Middle Aged, 16p11.2, Phenotype, Chromatin, [SDV] Life Sciences [q-bio], Child, Preschool, Knockout mouse, Female, Chromosomes, Human, Pair 16/genetics, Chromosome Deletion, Autistic Disorder/genetics, Signal Transduction, Adult, DNA Copy Number Variations, Adolescent, autism, Biology, Article, Young Adult, 03 medical and health sciences, Intellectual Disability, Zebrafish Proteins/genetics, medicine, Humans, Animals, Brain/metabolism, Autistic Disorder, Membrane Proteins/genetics, Adaptor Proteins, Signal Transducing, Aged, genome architecture, Membrane Proteins, Infant, Zebrafish Proteins, Phosphoproteins, medicine.disease, biology.organism_classification, Intellectual Disability/genetics, Mice, Inbred C57BL, 030104 developmental biology, Zebrafish/embryology, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery, Embryo, Nonmammalian/metabolism
Abstract: International audience; Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.
Published: 2017

33. Quantifying the effects of 16p11.2 copy number variants on brain structure: A multisite genetic-first study

Author: Sandra Martin-Brevet, Borja Rodríguez-Herreros, Jared A. Nielsen, Clara Moreau, Claudia Modenato, Anne M. Maillard, Aurélie Pain, Sonia Richetin, Aia E. Jønch, Abid Y. Qureshi, Nicole R. Zürcher, Philippe Conus, Wendy K. Chung, Elliott H. Sherr, John E. Spiro, Ferath Kherif, Jacques S. Beckmann, Nouchine Hadjikhani, Alexandre Reymond, Randy L. Buckner, Bogdan Draganski, Sébastien Jacquemont, Marie-Claude Addor, Joris Andrieux, Benoît Arveiler, Geneviève Baujat, Frédérique Sloan-Béna, Marco Belfiore, Dominique Bonneau, Sonia Bouquillon, Odile Boute, Alfredo Brusco, Tiffany Busa, Jean-Hubert Caberg, Dominique Campion, Vanessa Colombert, Marie-Pierre Cordier, Albert David, François-Guillaume Debray, Marie-Ange Delrue, Martine Doco-Fenzy, Ulrike Dunkhase-Heinl, Patrick Edery, Christina Fagerberg, Laurence Faivre, Francesca Forzano, David Genevieve, Marion Gérard, Daniela Giachino, Agnès Guichet, Olivier Guillin, Delphine Héron, Bertrand Isidor, Aurélia Jacquette, Sylvie Jaillard, Hubert Journel, Boris Keren, Didier Lacombe, Sébastien Lebon, Cédric Le Caignec, Marie-Pierre Lemaître, James Lespinasse, Michèle Mathieu-Dramart, Sandra Mercier, Cyril Mignot, Chantal Missirian, Florence Petit, Kristina Pilekær Sørensen, Lucile Pinson, Ghislaine Plessis, Fabienne Prieur, Caroline Rooryck-Thambo, Massimiliano Rossi, Damien Sanlaville, Britta Schlott Kristiansen, Caroline Schluth-Bolard, Marianne Till, Mieke Van Haelst, Lionel Van Maldergem, Hanalore Alupay, Benjamin Aaronson, Sean Ackerman, Katy Ankenman, Ayesha Anwar, Constance Atwell, Alexandra Bowe, Arthur L. Beaudet, Marta Benedetti, Jessica Berg, Jeffrey Berman, Leandra N. Berry, Audrey L. Bibb, Lisa Blaskey, Jonathan Brennan, Christie M. Brewton, Randy Buckner, Polina Bukshpun, Jordan Burko, Phil Cali, Bettina Cerban, Yishin Chang, Maxwell Cheong, Vivian Chow, Zili Chu, Darina Chudnovskaya, Lauren Cornew, Corby Dale, John Dell, Allison G. Dempsey, Trent Deschamps, Rachel Earl, James Edgar, Jenna Elgin, Jennifer Endre Olson, Yolanda L. Evans, Anne Findlay, Gerald D. Fischbach, Charlie Fisk, Brieana Fregeau, Bill Gaetz, Leah Gaetz, Silvia Garza, Jennifer Gerdts, Orit Glenn, Sarah E. Gobuty, Rachel Golembski, Marion Greenup, Kory Heiken, Katherine Hines, Leighton Hinkley, Frank I. Jackson, Julian Jenkins, Rita J. Jeremy, Kelly Johnson, Stephen M. Kanne, Sudha Kessler, Sarah Y. Khan, Matthew Ku, Emily Kuschner, Anna L. Laakman, Peter Lam, Morgan W. Lasala, Hana Lee, Kevin LaGuerre, Susan Levy, Alyss Lian Cavanagh, Ashlie V. Llorens, Katherine Loftus Campe, Tracy L. Luks, Elysa J. Marco, Stephen Martin, Alastair J. Martin, Gabriela Marzano, Christina Masson, Kathleen E. McGovern, Rebecca McNally Keehn, David T. Miller, Fiona K. Miller, Timothy J. Moss, Rebecca Murray, Srikantan S. Nagarajan, Kerri P. Nowell, Julia Owen, Andrea M. Paal, Alan Packer, Patricia Z. Page, Brianna M. Paul, Alana Peters, Danica Peterson, Annapurna Poduri, Nicholas J. Pojman, Ken Porche, Monica B. Proud, Saba Qasmieh, Melissa B. Ramocki, Beau Reilly, Timothy P.L. Roberts, Dennis Shaw, Tuhin Sinha, Bethanny Smith-Packard, Anne Snow Gallagher, Vivek Swarnakar, Tony Thieu, Christina Triantafallou, Roger Vaughan, Mari Wakahiro, Arianne Wallace, Tracey Ward, Julia Wenegrat, Anne Wolken, 16p11.2 European Consortium, Simons Variation in Individuals Project (VIP) Consortium, CSIR-Institute of Microbial Technology [Chandigarh] (IMTech), Council of Scientific and Industrial Research [India] (CSIR), Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Human Genetics, Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), The Wellcome Trust Sanger Institute [Cambridge], Department of Psychiatry [Boston], Massachusetts General Hospital [Boston], Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Humaine, Développement et Cancer, Université Bordeaux Segalen - Bordeaux 2, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Guglielmo Marconi University [Roma], Laboratoire de biomécanique (LBM), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Systèmes de Référence Temps Espace (SYRTE), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Medical Sciences, Università degli studi di Torino (UNITO), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), 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), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Liège (CHU-Liège), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Department of Clinical Genetics, Vejle Hospital, Institute of Child Health, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), 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), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, CHU Bordeaux [Bordeaux], Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Department of Genomics of Common Disease, Imperial College London, Regional Hospital, Department of Psychiatry and Behavioral Sciences! (UW psychiatry), University of Washington [Seattle], University of California, San Francisco (UCSF), UCSF, Unité de Recherches Zootechniques (URZ), Institut National de la Recherche Agronomique (INRA), University of California [San Francisco] (UCSF), University of California, UCL Institute of Neurology, Biomagnetic Imaging Laboratory - University of California, SFARI219193, Simons Foundation, 31003A160203, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Roger De Spoelberch, Partridge Foundations, Jeanne et Jean Louis Levesque Foundation, 604102, Seventh Framework Programme, Canada Research Chairs, CRSII33-133044, SNSF Sinergia, 32003B_159780, SNSF National Centre of Competence in Research Synapsy, Foundation Parkinson Switzerland, Foundation Synapsis, Université de Lausanne = University of Lausanne (UNIL), CHU Sainte Justine [Montréal], Harvard University [Cambridge], Odense University Hospital (OUH), Department of radiology (Massachusetts General Hospital), Department of Psychiatry Massachusetts General Hospital (MGH), Columbia University [New York], Simons Foundation, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Gothenburg (GU), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Torino = University of Turin (UNITO), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vejle Hospital [Danemark], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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 Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), École normale supérieure - Lyon (ENS Lyon)-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), Harvard University, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), University of Lausanne (UNIL), Centre de recherche du CHU Sainte-Justine [Montreal], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Human genetics, Institute of Microbial Technology (IMTECH), Intitute of Microbial Technology, Gillberg Neuropsychiatry Centre, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], PSL Research University (PSL)-PSL Research University (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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 [APHP], Centre Hospitalier Bretagne Atlantique-Hôpital Chubert, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [APHP], Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Addor, M.C., Andrieux, J., Arveiler, B., Baujat, G., Sloan-Béna, F., Belfiore, M., Bonneau, D., Bouquillon, S., Boute, O., Brusco, A., Busa, T., Caberg, J.H., Campion, D., Colombert, V., Cordier, M.P., David, A., Debray, F.G., Delrue, M.A., Doco-Fenzy, M., Dunkhase-Heinl, U., Edery, P., Fagerberg, C., Faivre, L., Forzano, F., Genevieve, D., Gérard, M., Giachino, D., Guichet, A., Guillin, O., Héron, D., Isidor, B., Jacquette, A., Jaillard, S., Journel, H., Keren, B., Lacombe, D., Lebon, S., Le Caignec, C., Lemaître, M.P., Lespinasse, J., Mathieu-Dramart, M., Mercier, S., Mignot, C., Missirian, C., Petit, F., Pilekær Sørensen, K., Pinson, L., Plessis, G., Prieur, F., Rooryck-Thambo, C., Rossi, M., Sanlaville, D., Schlott Kristiansen, B., Schluth-Bolard, C., Till, M., Van Haelst, M., Van Maldergem, L., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Anwar, A., Atwell, C., Bowe, A., Beaudet, A.L., Benedetti, M., Berg, J., Berman, J., Berry, L.N., Bibb, A.L., Blaskey, L., Brennan, J., Brewton, C.M., Buckner, R., Bukshpun, P., Burko, J., Cali, P., Cerban, B., Chang, Y., Cheong, M., Chow, V., Chu, Z., Chudnovskaya, D., Cornew, L., Dale, C., Dell, J., Dempsey, A.G., Deschamps, T., Earl, R., Edgar, J., Elgin, J., Olson, J.E., Evans, Y.L., Findlay, A., Fischbach, G.D., Fisk, C., Fregeau, B., Gaetz, B., Gaetz, L., Garza, S., Gerdts, J., Glenn, O., Gobuty, S.E., Golembski, R., Greenup, M., Heiken, K., Hines, K., Hinkley, L., Jackson, F.I., Jenkins, J., Jeremy, R.J., Johnson, K., Kanne, S.M., Kessler, S., Khan, S.Y., Ku, M., Kuschner, E., Laakman, A.L., Lam, P., Lasala, M.W., Lee, H., LaGuerre, K., Levy, S., Cavanagh, A.L., Llorens, A.V., Campe, K.L., Luks, T.L., Marco, E.J., Martin, S., Martin, A.J., Marzano, G., Masson, C., McGovern, K.E., McNally Keehn, R., Miller, D.T., Miller, F.K., Moss, T.J., Murray, R., Nagarajan, S.S., Nowell, K.P., Owen, J., Paal, A.M., Packer, A., Page, P.Z., Paul, B.M., Peters, A., Peterson, D., Poduri, A., Pojman, N.J., Porche, K., Proud, M.B., Qasmieh, S., Ramocki, M.B., Reilly, B., Roberts, TPL, Shaw, D., Sinha, T., Smith-Packard, B., Gallagher, A.S., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., and Wolken, A.
Subjects: Adult, Male, 0301 basic medicine, Adolescent, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Autism Spectrum Disorder/diagnostic imaging, Autism Spectrum Disorder/genetics, Brain/pathology, Child, Chromosome Deletion, Chromosome Duplication, Chromosomes, Human, Pair 16/genetics, Cognitive Dysfunction/diagnostic imaging, Cognitive Dysfunction/genetics, Female, Humans, Intellectual Disability/diagnostic imaging, Intellectual Disability/genetics, Language, Magnetic Resonance Imaging, Middle Aged, Neurodevelopmental Disorders/diagnostic imaging, Neurodevelopmental Disorders/genetics, Schizophrenia/diagnostic imaging, Schizophrenia/genetics, Young Adult, 16p11.2, Autism spectrum disorder, Copy number variant, Genetics, Imaging, Neurodevelopmental disorders, Biology, Biological Psychiatry, 03 medical and health sciences, 0302 clinical medicine, Transverse temporal gyrus, Neuroimaging, Intellectual Disability, medicine, Cognitive Dysfunction, Copy-number variation, ComputingMilieux_MISCELLANEOUS, Brain morphometry, Brain, medicine.disease, 16p112, 030104 developmental biology, Schizophrenia, Williams syndrome, Neuroscience, Insula, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery
Abstract: BACKGROUND: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure.METHODS: Using voxel- and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV.RESULTS: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion > control > duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion > control; Cohen's d > 1), the superior and middle temporal gyri (deletion < control; Cohen's d < -1), and the caudate and hippocampus (control > duplication; -0.5 > Cohen's d > -1). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results.CONCLUSIONS: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria.
Published: 2018

34. A framework for the investigation of rare genetic disorders in neuropsychiatry

Author: Meera E. Modi, Stephen Sanders, Guoping Feng, Paul Avillach, Carrie E. Bearden, Anne Pariser, Thomas Lehner, Andres Moreno-De-Luca, Audrey Thurm, David H. Ledbetter, Raquel E. Gur, Elise Douard, Jonathan Sebat, Joseph Hostyk, Ricardo E. Dolmetsch, David B. Goldstein, Daniel H. Geschwind, Christa Lese Martin, David C. Glahn, Sébastien Jacquemont, Armin Raznahan, Mustafa Sahin, Rodney C. Samaco, Alan Anticevic, Jennifer G. Mulle, Sergiu P. Paşca, McGovern Institute for Brain Research at MIT, and Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Subjects: 0301 basic medicine, Immunology, Genomics, Neuropsychiatry, Medical and Health Sciences, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, Genetics, Medicine, Humans, Genetic risk, Cognitive science, business.industry, Extramural, Mental Disorders, Human Genome, Neurosciences, General Medicine, Human morbidity, Data sharing, 030104 developmental biology, Mental Health, 030220 oncology & carcinogenesis, Identification (biology), business
Abstract: De novo and inherited rare genetic disorders (RGDs) are a major cause of human morbidity, frequently involving neuropsychiatric symptoms. Recent advances in genomic technologies and data sharing have revolutionized the identification and diagnosis of RGDs, presenting an opportunity to elucidate the mechanisms underlying neuropsychiatric disorders by investigating the pathophysiology of high-penetrance genetic risk factors. Here we seek out the best path forward for achieving these goals. We think future research will require consistent approaches across multiple RGDs and developmental stages, involving both the characterization of shared neuropsychiatric dimensions in humans and the identification of neurobiological commonalities in model systems. A coordinated and concerted effort across patients, families, researchers, clinicians and institutions, including rapid and broad sharing of data, is now needed to translate these discoveries into urgently needed therapies. Rare genetic diseases frequently involve a neuropsychiatric component for which a defined framework of investigation will expedite our understanding for these diseases as a whole.
Published: 2018

35. Mitochondrial tRNALeu(UUR) mutation m.3302A > G presenting as childhood-onset severe myopathy: threshold determination through segregation study

Author: Sébastien Jacquemont, Pierre-Yves Jeannet, Frederic Guerry, Diana Ballhausen, André Schaller, Luisa Bonafé, Jean-Marc Nuoffer, and Dagmar Hahn
Subjects: Male, medicine.medical_specialty, Pathology, RNA, Mitochondrial, Biopsy, Buccal swab, DNA Mutational Analysis, Biology, Asymptomatic, Severity of Illness Index, Oxidative Phosphorylation, Quadriceps Muscle, RNA, Transfer, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Age of Onset, Myopathy, Child, Genetics (clinical), Cells, Cultured, Homoplasmy, Muscle Weakness, Muscular hypotonia, Respiratory chain complex, Mitochondrial Myopathies, medicine.disease, Heteroplasmy, Pedigree, Endocrinology, Phenotype, Lactic acidosis, Mutation, Disease Progression, RNA, Female, medicine.symptom, Energy Metabolism
Abstract: Mitochondrial tRNA(Leu(UUR)) mutation m.3302A > G is associated with respiratory chain complex I deficiency and has been described as a rare cause of mostly adult-onset slowly progressive myopathy. Five families with 11 patients have been described so far; 5 of them died young due to cardiorespiratory failure. Here, we report on a segregation study in a family with an index patient who already presented at the age of 18 months with proximal muscular hypotonia, abnormal fatigability, and lactic acidosis. This early-onset myopathy was rapidly progressive. At 8 years, the patient is wheel-chair bound, requires nocturnal assisted ventilation, and suffers from recurrent respiratory infections. Severe complex I deficiency and nearly homoplasmy for m.3302A > G were found in muscle. We collected blood, hair, buccal swabs and muscle biopsies from asymptomatic adults in this pedigree and determined heteroplasmy levels in these tissues as well as OXPHOS activities in muscle. All participating asymptomatic adults had normal OXPHOS activities. In contrast to earlier reports, we found surprisingly little variation of heteroplasmy levels in different tissues of the same individual. Up to 45% mutation load in muscle and up to 38% mutation load in other tissues were found in non-affected adults. The phenotypic spectrum of tRNA(Leu(UUR)) m.3302A > G mutation seems to be wider than previously described. A threshold of more than 45% heteroplasmy in muscle seems to be necessary to alter complex I activity leading to clinical manifestation. The presented data may be helpful for prognostic considerations and counseling in affected families.
Published: 2018

36. M57 THE IMPACT OF COPY NUMBER VARIANTS ON BRAIN MORPHOMETRY

Author: Sébastien Jacquemont, Lester Melie-Garcia, Clara Moreau, Borja Rodriguez-Herreros, Carrie E. Bearden, Claudia Modenato, Sonia Richetin, Bogdan Draganski, Kuldeep Kumar, Aurélie Pain, Catherine Schramm, Sandra Martin-Brevet, Guillaume Huguet, Anne M. Maillard, and Eloi Gagnon
Subjects: Pharmacology, Genetics, Psychiatry and Mental health, Neurology, Brain morphometry, Pharmacology (medical), Neurology (clinical), Copy-number variation, Biology, Biological Psychiatry
Published: 2019

37. 6 DIFFERENTIAL EFFECTS OF DELETIONS AND DUPLICATIONS ON AUTISM RISK ACROSS THE GENOME

Author: Tomáš Paus, Sabrina Nowak, Thomas Bourgeron, Petra Tamer, Mor Absa Loum, Guillaume Huguet, David C. Glahn, Sébastien Jacquemont, Gunter Schumann, Eva Loth, Catherine Schramm, Abderrahim Zeribi, Celia M. T. Greenwood, Laurent Mottron, and Elise Douard
Subjects: Pharmacology, Genetics, Psychiatry and Mental health, Neurology, medicine, Autism, Pharmacology (medical), Neurology (clinical), Biology, medicine.disease, Differential effects, Genome, Biological Psychiatry
Published: 2019

38. A GENETIC FIRST APPROACH TO DISSECTING THE HETEROGENEITY OF AUTISM: PHENOTYPIC COMPARISON OF AUTISM RISK COPY NUMBER VARIANTS

Author: Wendy K. Chung, Carrie E. Bearden, Wendy R. Kates, Joanne L. Doherty, Hayley Moss, Michael John Owen, Jacob A. S. Vorstman, Sarah Curran, Jeremy Hall, Sébastien Jacquemont, Samuel J.R.A. Chawner, and Marianne Bernadette van den Bree
Subjects: Pharmacology, Genetics, Intelligence quotient, business.industry, Genetic variants, medicine.disease, behavioral disciplines and activities, Phenotype, 030227 psychiatry, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Neurology, mental disorders, Genotype, Gene duplication, medicine, Autism, Pharmacology (medical), Neurology (clinical), Copy-number variation, business, 030217 neurology & neurosurgery, Biological Psychiatry
Abstract: Background Autism is a heterogeneous condition and there is growing evidence that different features are dissociable and may be underpinned by different risk factors. Several autism risk copy number variants (CNVs) have been identified. It remains unclear whether these CNVs differentially impact autism presentation. This study aimed to contrast autism symptomatology and the clinical profile of different autism risk CNVs. Methods Patients were recruited at several international sites based on genotype, not autism phenotype. This work represents the efforts of several consortia; the ECHO study, IMAGINE-ID consortium, International 22q11.2DS Brain Behaviour Consortium, 16p11.2 European Consortium and Simons VIP. Patients were all assessed using the Autism Diagnostic Interview-Revised (ADI-R) and underwent IQ testing. We focused on 16p11.2 deletion (n=96), 16p11.2 duplication (n=47), 22q11.2 deletion (n=383) and 22q11.2 duplication (n=22) carriers. Patients were aged 4–27 years. We examined autism prevalence based on ADI-R criteria, ADI-R domain scores, whether carriers with autism had additional IQ deficits and autism male-to-female ratio. Results Autism prevalence differed by syndrome (p Discussion Autism risk genetic variants have specific genotype-phenotype correlations. This indicates that autism is dissociable at the genetic level, and supports the view that different biological pathways underpin distinct symptom domains.
Published: 2019

39. CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits

Author: Ruth J. F. Loos, Alexandre Reymond, Daniele Cusi, Veikko Salomaa, Martina Müller-Nurasyid, Anne B. Newman, Katja Borodulin, Andrew R. Wood, Mika Kähönen, Michael N. Weedon, John C. Chambers, Sébastien Jacquemont, Rachel M. Freathy, Iris M. Heid, Murielle Bochud, Ilja M. Nolte, Aarno Palotie, Thomas Meitinger, Jennifer Kriebel, Harold Snieder, Caroline Hayward, Harri Rissanen, Anna Murray, Timothy M. Frayling, Frank Geller, Mads Melbye, Erika Salvi, Jacques S. Beckmann, Harmen Boers, Mary F. Feitosa, Jorma Viikari, Lude Franke, Wei Ang, Marja-Liisa Lokki, Marcus A. Tuke, Guillaume Lettre, Samuel E. Jones, Jari Lahti, Hannele Mattsson, Tim D. Spector, Aaron McDaid, Nicholas G. Martin, David P. Strachan, Martin D. Tobin, Kaare Christensen, Jessica Tyrrell, Johan G. Eriksson, Saima Afaq, Cristina Venturini, Jaspal S. Kooner, Fernando Rivadeneira, Louise V. Wain, Weihua Zhang, Zoltán Kutalik, Reedik Mägi, Olli T. Raitakari, Joel N. Hirschhorn, Satu Männistö, Nick Shrine, Seppo Koskinen, Robin N Beaumont, Margit Nõukas, Xueping Liu, Yadav Sapkota, Michael A. Province, Thomas T. Perls, Markus Perola, Massimo Mangino, Nicole Schupf, Aurélien Macé, Anders Rosengren, Naomi R. Wray, Katrin Männik, Sarah E. Medland, Aki S. Havulinna, David J. Porteous, Craig E. Pennell, Katherine S. Ruth, Albertine J. Oldehinkel, Petra A. Lenzini, Thomas Hansen, Peter J. van der Most, Thomas W. Winkler, Thomas Sparsø, Markku S. Nieminen, Annette Peters, Mary K. Wojczynski, P Koponen, Patrick Deelen, Dale R. Nyholt, Hanieh Yaghootkar, Erwin P. Bottinger, Juha Sinisalo, Kati Kristiansson, Grant W. Montgomery, Thomas Werge, Terho Lehtimäki, Bjarke Feenstra, Erkki Vartiainen, Eleonora Porcu, Panos Deloukas, Sina Rüeger, Ursula M. Schick, Annamari Lundqvist, Andres Metspalu, Morris A. Swertz, Institute for Molecular Medicine Finland, University of Helsinki, Quantitative Genetics, Complex Disease Genetics, Doctoral Programme in Biomedicine, Doctoral Programme in Population Health, University Management, Doctoral Programme in Drug Research, HUS Heart and Lung Center, Clinicum, Biosciences, Medicum, Department of Psychology and Logopedics, Helsinki Collegium for Advanced Studies, Developmental Psychology Research Group, Doctoral Programme in Clinical Research, Research Programs Unit, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Doctoral Programme Brain & Mind, Department of Diagnostics and Therapeutics, Department of Medicine, Department of Public Health, Faculty of Arts, Department of General Practice and Primary Health Care, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Doctoral Programme in Oral Sciences, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: 0301 basic medicine, endocrine system diseases, Chromosomes, Human, Pair 22, General Physics and Astronomy, Genome-wide association study, VARIANTS, Body Mass Index, Body Size, lcsh:Science, 10. No inequality, 2. Zero hunger, Genetics, Multidisciplinary, Anthropometry, DEVELOPMENTAL DELAY, WILLIAMS-BEUREN-SYNDROME, ANTHROPOMETRIC MEASUREMENTS, Multidisciplinary Sciences, Phenotype, Chromosomes, Human, Pair 1, OBESITY, Science & Technology - Other Topics, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 7, congenital, hereditary, and neonatal diseases and abnormalities, MICRODUPLICATION, DNA Copy Number Variations, Genotype, Science, CNV, SNP, waist-to-hip ratio, Single-nucleotide polymorphism, Biology, Quantitative trait locus, White People, Article, General Biochemistry, Genetics and Molecular Biology, Structural variation, BMI, 03 medical and health sciences, MD Multidisciplinary, mental disorders, Journal Article, Humans, GENOME-WIDE ASSOCIATION, Human height, Science & Technology, Height, Waist-Hip Ratio, Chromosomes, Human, Pair 11, Body Weight, DELETION SYNDROME, weight, General Chemistry, Heritability, Body Height, Computational biology and bioinformatics, Genome-wide association studies, Quantitative trait, BODY-MASS INDEX, 030104 developmental biology, lcsh:Q, 3111 Biomedicine, Chromosomes, Human, Pair 18, HUMAN HEIGHT, Body mass index, Chromosomes, Human, Pair 16, Genome-Wide Association Study, Body Height/genetics, Body Size/genetics, Body Weight/genetics, Chromosomes, Human, Pair 1/genetics, Chromosomes, Human, Pair 11/genetics, Chromosomes, Human, Pair 16/genetics, Chromosomes, Human, Pair 18/genetics, Chromosomes, Human, Pair 22/genetics, Chromosomes, Human, Pair 3/genetics, Chromosomes, Human, Pair 7/genetics, European Continental Ancestry Group/genetics
Abstract: There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01–0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m2). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 × 10−10, 6.0 × 10−5, and 2.9 × 10−3). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders., Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.
Published: 2017

40. A higher mutational burden in females supports a 'female protective model' in neurodevelopmental disorders

Author: Jacques S. Beckmann, Sven Bergmann, Sébastien Jacquemont, Bradley P. Coe, Michael H. Duyzend, Micha Hersch, Evan E. Eichler, Jill A. Rosenfeld, and Niklas Krumm
Subjects: Adult, Male, Proband, Chromosomes, Artificial, Bacterial, Adolescent, DNA Copy Number Variations, Genotype, Developmental Disabilities, DNA Mutational Analysis, Biology, Polymorphism, Single Nucleotide, Article, Cohort Studies, Young Adult, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Polymorphism (computer science), Databases, Genetic, mental disorders, Odds Ratio, Genetics, medicine, Humans, Genetics(clinical), Genetics (clinical), X chromosome, Aged, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, 0303 health sciences, Odds ratio, Middle Aged, medicine.disease, Markov Chains, Phenotype, Child Development Disorders, Pervasive, Autism spectrum disorder, Mutation, Cohort, Female, Cognition Disorders, Gene Deletion, 030217 neurology & neurosurgery, Cohort study
Abstract: Increased male prevalence has been repeatedly reported in several neurodevelopmental disorders (NDs), leading to the concept of a "female protective model." We investigated the molecular basis of this sex-based difference in liability and demonstrated an excess of deleterious autosomal copy-number variants (CNVs) in females compared to males (odds ratio [OR] = 1.46, p = 8 × 10(-10)) in a cohort of 15,585 probands ascertained for NDs. In an independent autism spectrum disorder (ASD) cohort of 762 families, we found a 3-fold increase in deleterious autosomal CNVs (p = 7 × 10(-4)) and an excess of private deleterious single-nucleotide variants (SNVs) in female compared to male probands (OR = 1.34, p = 0.03). We also showed that the deleteriousness of autosomal SNVs was significantly higher in female probands (p = 0.0006). A similar bias was observed in parents of probands ascertained for NDs. Deleterious CNVs (400 kb) were maternally inherited more often (up to 64%, p = 10(-15)) than small CNVs400 kb (OR = 1.45, p = 0.0003). In the ASD cohort, increased maternal transmission was also observed for deleterious CNVs and SNVs. Although ASD females showed higher mutational burden and lower cognition, the excess mutational burden remained, even after adjustment for those cognitive differences. These results strongly suggest that females have an increased etiological burden unlinked to rare deleterious variants on the X chromosome. Carefully phenotyped and genotyped cohorts will be required for identifying the symptoms, which show gender-specific liability to mutational burden.
Published: 2014
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41. 188. ENIGMA-CNV: Unraveling the Effects of Rare Copy Number Variants on Brain Structure

Author: Hreinn Stefansson, Lars T. Westlye, Srdjan Djurovic, Bragi Walters, Paul M. Thompson, Sébastien Jacquemont, Ida E Sønderby, Dennis van der Meer, Ingrid Agartz, and Ole A. Andreassen
Subjects: Genetics, Copy-number variation, Biology, Biological Psychiatry
Published: 2019

42. QUANTIFYING THE EFFECT OF COPY-NUMBER VARIANTS ON GENERAL INTELLIGENCE IN UNSELECTED POPULATIONS

Author: Elise Douard, Lai Jiang, Tomáš Paus, Thomas Bourgeron, Roberto Toro, Patricia J. Conrod, Sébastien Jacquemont, Guillaume Huguet, Gunter Schumann, Aurélie Labbe, Jean-Baptiste Poline, Zdenka Pausova, Catherine Schramm, Celia M. T. Greenwood, and Eva Loth
Subjects: Pharmacology, Genetics, congenital, hereditary, and neonatal diseases and abnormalities, education.field_of_study, endocrine system diseases, Verbal intelligence quotient, Population, Disease, Biology, Psychiatry and Mental health, Neurology, mental disorders, Mutation (genetic algorithm), Pharmacology (medical), In patient, Neurology (clinical), Copy-number variation, education, Genotyping, Biological Psychiatry, Youth study
Abstract: Background Detection of Copy Number Variants (CNVs) are routinely performed in patients with Neurodevelopmental Disorders (NDs) and “Clinically significant” CNVs, defined as rare and large CNVs contributing to disease, are identified in 10 to 15% of patients. Effects of these clinically significant CNVs on cognitive traits have been studied for only a small number of recurrent CNVs. In addition, case-control studies are impossible to perform for > 75% of CNVs that are non-recurrent. As a result, their effects on neurodevelopment are neither characterized nor understood. Objectives: To examine the effect of CNVs on measures of Performance and Verbal Intelligence Quotient (PIQ and VIQ) in general populations. To model and predict the effect of CNVs on PIQ and VIQ using variables that characterize gene content and noncoding regions involved in CNVs. Methods We called CNVs from genotyping data with PennCNV and QuantiSNP on two cohorts drawn for the general population: Imagen (n=1804) and the Saguenay Youth Study (n=968). Rare ( Results We identified rare deletion and duplications larger than 250 kb in 10% of individuals. Both the size and gene content of rare deletions decrease IQ, eg. deletions ≥250Kb decrease IQ by 6 points (p=2.10–3). We were unable to detect a significant effect of rare duplications on IQ. For estimating the effect of all deletions on IQ, a stepwise linear model procedure converged on a model including mutation intolerance scores (pvalue 80%, p≤2.10–3). Discussion Our results suggest that the effects of deletions on general intelligence can be reliably modeled and represent a new perspective for the study of non-recurrent CNVs. These results will also help clinicians estimate the impact of non-recurrent CNVs on cognition in their patients.
Published: 2019

43. SCRIB and PUF60 Are Primary Drivers of the Multisystemic Phenotypes of the 8q24.3 Copy-Number Variant

Author: Jacques S. Beckmann, Christelle Golzio, Nicholas Katsanis, Andrew Dauber, Małgorzata J.M. Nowaczyk, Susan Zeesman, Joel N. Hirschhorn, Francine M. Jodelka, Jill A. Rosenfeld, Danielle Martinet, Bruno Leheup, Cécile Guenot, Michelle L. Hastings, Susanne Kjaergaard, Sébastien Jacquemont, Janice Zunich, Maria Kibaek, UL, NGERE, Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Harvard Medical School [Boston] (HMS), Broad Institute [Cambridge], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Center for Human Disease Modeling, Duke University [Durham], Service de Génétique Médicale [CHUV Lausanne], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Service de Génétique Clinique [CHUV Lausanne], Department of Cell Biology and Anatomy [Chicago Medical School · Rosalind Franklin University], Chicago Medical School [Rosalind Franklin University], Rosalind Franklin University-Rosalind Franklin University, Department of Pediatrics [Odense University Hospital], Odense University Hospital, Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), McMaster University [Hamilton, Ontario], PerkinElmer, Inc., Indiana University School of Medicine, Indiana University System-Indiana University System, and Dept of Genetics, Harvard Medical School
Subjects: Male, Microcephaly, Developmental Disabilities, [SDV]Life Sciences [q-bio], medicine.disease_cause, 0302 clinical medicine, Genetics(clinical), Copy-number variation, Child, Zebrafish, Genetics (clinical), Genetics, 0303 health sciences, Mutation, Chromosome Mapping, RNA-Binding Proteins, Phenotype, [SDV] Life Sciences [q-bio], Child, Preschool, Gene Knockdown Techniques, RNA splicing, Female, RNA Splicing Factors, Erratum, Chromosomes, Human, Pair 8, SCRIB, Adolescent, DNA Copy Number Variations, Biology, Article, 03 medical and health sciences, Intellectual Disability, medicine, Animals, Humans, Allele, Alleles, 030304 developmental biology, Tumor Suppressor Proteins, Membrane Proteins, medicine.disease, Human genetics, Genetic architecture, Repressor Proteins, Gene Deletion, 030217 neurology & neurosurgery, HeLa Cells
Abstract: International audience; Copy-number variants (CNVs) represent a significant interpretative challenge, given that each CNV typically affects the dosage of multiple genes. Here we report on five individuals with coloboma, microcephaly, developmental delay, short stature, and craniofacial, cardiac, and renal defects who harbor overlapping microdeletions on 8q24.3. Fine mapping localized a commonly deleted 78 kb region that contains three genes: SCRIB, NRBP2, and PUF60. In vivo dissection of the CNV showed discrete contributions of the planar cell polarity effector SCRIB and the splicing factor PUF60 to the syndromic phenotype, and the combinatorial suppression of both genes exacerbated some, but not all, phenotypic components. Consistent with these findings, we identified an individual with microcephaly, short stature, intellectual disability, and heart defects with a de novo c.505C>T variant leading to a p.His169Tyr change in PUF60. Functional testing of this allele in vivo and in vitro showed that the mutation perturbs the relative dosage of two PUF60 isoforms and, subsequently, the splicing efficiency of downstream PUF60 targets. These data inform the functions of two genes not associated previously with human genetic disease and demonstrate how CNVs can exhibit complex genetic architecture, with the phenotype being the amalgam of both discrete dosage dysfunction of single transcripts and also of binary genetic interactions.
Published: 2013

44. Transmission Disequilibrium of Small CNVs in Simplex Autism

Author: Jeff Munson, Laura Vives, Ben Nelson, Evan E. Eichler, Sébastien Jacquemont, Brian J. O'Roak, Niklas Krumm, Raphe Bernier, Emre Karakoc, and Kiana Mohajeri
Subjects: Proband, Male, Risk, Linkage disequilibrium, congenital, hereditary, and neonatal diseases and abnormalities, endocrine system diseases, DNA Copy Number Variations, Gene Expression, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, mental disorders, medicine, Genetics, SNP, Humans, Exome, Genetic Predisposition to Disease, Genetics(clinical), Sibling, Child, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Siblings, Odds ratio, medicine.disease, Phenotype, Autism spectrum disorder, Child Development Disorders, Pervasive, Autism, Female, 030217 neurology & neurosurgery
Abstract: We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ∼2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands’ CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD.
Published: 2013
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45. Implication of LRRC4C and DPP6 in neurodevelopmental disorders

Author: Colby Chiang, Steve McCarroll, Gilles Maussion, Jin P. Szatkiewicz, Sébastien Jacquemont, Scott C. Bell, Colm O'Dushlaine, Michael E. Talkowski, Christina M. Hultman, Carrie Hanscom, Gustavo Turecki, Carl Ernst, Vanessa Kiyomi Ota, Dimitri J. Stavropoulos, Christian R. Marshall, Patrick F. Sullivan, Melissa T. Carter, Cynthia C. Morton, Martin Alda, Ian Blumenthal, Ilaria Kolobova, Nicolas Menjot de Champfleur, Jill A. Rosenfeld, Cristiana Cruceanu, Santhosh Girirajan, Ryan L. Collins, Stephen W. Scherer, James F. Gusella, Pamela Sklar, Zehra Ordulu, Fabrice Jollant, Lisa G. Shaffer, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département de Neuroradiologie[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), and Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Proband, Untranslated region, Male, Potassium Channels, Gene Expression, Translocation, Genetic, Exon, Chromosome Breakpoints, Netrin, sensory processing, Child, Genetics (clinical), Chromosomal inversion, Genetics, Comparative Genomic Hybridization, Netrin G, High-Throughput Nucleotide Sequencing, Middle Aged, Phenotype, Pedigree, Child, Preschool, Multigene Family, Female, Adult, Adolescent, DNA Copy Number Variations, Apraxias, Karyotype, autism, DPP6, Nerve Tissue Proteins, Receptors, Cell Surface, Biology, Article, 03 medical and health sciences, Young Adult, medicine, Humans, Autistic Disorder, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Genetic Association Studies, Gene Expression Profiling, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Chromosome Inversion, Autism, Axon guidance, 5' Untranslated Regions, LRRC4C, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11.2, 1q44, and 2q33.1 CN syndromes, suggesting LRRC4C deletion variants may be modifiers of neurodevelopmental disorders. In vitro, functional assessments modeling patient deletions in LRRC4C suggest a negative regulatory role of these exons found in the untranslated region of LRRC4C, which has a single, terminal coding exon. These data suggest that the proband's autism may be due to the inheritance of disruptions in both DPP6 and LRRC4C, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders. © 2016 Wiley Periodicals, Inc.
Published: 2016

46. Sex chromosome aneuploidies and copy-number variants: a further explanation for neurodevelopmental prognosis variability?

Author: Albert David, Sylvie Jaillard, Brigitte Gilbert-Dussardier, Mélanie Fradin, Olivier Pichon, Sébastien Moutton, Tiffany Busa, Elise Schaefer, Sandra Mercier, Frédéric Bilan, Odile Boute, Sabine Baron, Sébastien Jacquemont, Caroline Rooryck, Mathilde Nizon, Bertrand Isidor, Dominique Martin-Coignard, Joris Andrieux, Valérie Cormier-Daire, Séverine Audebert-Bellanger, Jessica Le Gall, Cédric Le Caignec, Damien Sanlaville, Claire Beneteau, Claude Férec, Marie Vincent, and Aia E. Jønch
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Pediatrics, DNA Copy Number Variations, Developmental Disabilities, Sex Chromosome Disorders of Sex Development, Sex Chromosome Disorders, Trisomy, Triple X syndrome, Biology, Article, 03 medical and health sciences, Neurodevelopmental disorder, Intellectual Disability, Intellectual disability, XYY Karyotype, Genetics, medicine, Humans, Copy-number variation, Genetics (clinical), Sex Chromosome Aberrations, Chromosomes, Human, X, Cytogenetics, medicine.disease, Human genetics, 030104 developmental biology, Phenotype, Medical genetics, XYY syndrome, Female
Abstract: Sex chromosome aneuploidies (SCA) is a group of conditions in which individuals have an abnormal number of sex chromosomes. SCA, such as Klinefelter’s syndrome, XYY syndrome, and Triple X syndrome are associated with a large range of neurological outcome. Another genetic event such as another cytogenetic abnormality may explain a part of this variable expressivity. In this study, we have recruited fourteen patients with intellectual disability or developmental delay carrying SCA associated with a copy-number variant (CNV). In our cohort (four patients 47,XXY, four patients 47,XXX, and six patients 47,XYY), seven patients were carrying a pathogenic CNV, two a likely pathogenic CNV and five a variant of uncertain significance. Our analysis suggests that CNV might be considered as an additional independent genetic factor for intellectual disability and developmental delay for patients with SCA and neurodevelopmental disorder.
Published: 2016

47. Reciprocal changes in DNA methylation and hydroxymethylation and a broad repressive epigenetic switch characterize FMR1 transcriptional silencing in fragile X syndrome

Author: Rémi Terranova, Christine McCormack, Fabrizio Gasparini, Olivier Grenet, Thomas Peters, Baltazar Gomez-Mancilla, Izabela Rozenberg, Sébastien Jacquemont, Arne Mueller, Yunsheng He, Sarah Brasa, Salah-Dine Chibout, Jonathan G. Moggs, and Florian Hahne
Subjects: 0301 basic medicine, Adult, Epigenomics, Genetic Markers, Male, Chromatin Immunoprecipitation, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, 5-hydroxymethylation (5hmC), Biology, Epigenesis, Genetic, 03 medical and health sciences, Fragile X Mental Retardation Protein, Young Adult, 0302 clinical medicine, RNA interference, Genetics, medicine, Gene silencing, Humans, Epigenetics, Gene Silencing, Child, Molecular Biology, Genetics (clinical), Loss function, Research, Clinical biomarker, Epigenetic silencing, FMR1, DNA Methylation, Middle Aged, medicine.disease, FMR1, nervous system diseases, Fragile X syndrome, 030104 developmental biology, Fragile X Syndrome, DNA methylation, Chromatin profiling, RNA Interference, 030217 neurology & neurosurgery, Fragile X syndrome (FXS), Developmental Biology
Abstract: Background Fragile X syndrome (FXS) is the most common form of inherited intellectual disability, resulting from the loss of function of the fragile X mental retardation 1 (FMR1) gene. The molecular pathways associated with FMR1 epigenetic silencing are still elusive, and their characterization may enhance the discovery of novel therapeutic targets as well as the development of novel clinical biomarkers for disease status. Results We have deployed customized epigenomic profiling assays to comprehensively map the FMR1 locus chromatin landscape in peripheral mononuclear blood cells (PBMCs) from eight FXS patients and in fibroblast cell lines derived from three FXS patient. Deoxyribonucleic acid (DNA) methylation (5-methylcytosine (5mC)) and hydroxymethylation (5-hydroxymethylcytosine (5hmC)) profiling using methylated DNA immunoprecipitation (MeDIP) combined with a custom FMR1 microarray identifies novel regions of DNA (hydroxy)methylation changes within the FMR1 gene body as well as in proximal flanking regions. At the region surrounding the FMR1 transcriptional start sites, increased levels of 5mC were associated to reciprocal changes in 5hmC, representing a novel molecular feature of FXS disease. Locus-specific validation of FMR1 5mC and 5hmC changes highlighted inter-individual differences that may account for the expected DNA methylation mosaicism observed at the FMR1 locus in FXS patients. Chromatin immunoprecipitation (ChIP) profiling of FMR1 histone modifications, together with 5mC/5hmC and gene expression analyses, support a functional relationship between 5hmC levels and FMR1 transcriptional activation and reveal cell-type specific differences in FMR1 epigenetic regulation. Furthermore, whilst 5mC FMR1 levels positively correlated with FXS disease severity (clinical scores of aberrant behavior), our data reveal for the first time an inverse correlation between 5hmC FMR1 levels and FXS disease severity. Conclusions We identify novel, cell-type specific, regions of FMR1 epigenetic changes in FXS patient cells, providing new insights into the molecular mechanisms of FXS. We propose that the combined measurement of 5mC and 5hmC at selected regions of the FMR1 locus may significantly enhance FXS clinical diagnostics and patient stratification. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0181-x) contains supplementary material, which is available to authorized users.
Published: 2016

48. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant

Author: Yu Taniguchi, Alexandre Reymond, Atsushi Kamiya, James F. Gusella, Sébastien Jacquemont, Michael E. Talkowski, Akira Sawa, Jason R. Willer, Mei Sun, Edwin C. Oh, Jacques S. Beckmann, Christelle Golzio, and Nicholas Katsanis
Subjects: Microcephaly, DNA Copy Number Variations, Transcription, Genetic, Gene Dosage, Apoptosis, Genomics, Locus (genetics), Biology, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Gene Duplication, Gene duplication, medicine, Animals, Humans, RNA, Messenger, Copy-number variation, Zebrafish, Cell Proliferation, Sequence Deletion, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Macrocephaly, Nuclear Proteins, Organ Size, medicine.disease, biology.organism_classification, Phenotype, Up-Regulation, medicine.symptom, Head, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery
Abstract: Copy number variants (CNVs) are major contributors to genetic disorders. We have dissected a region of the 16p11.2 chromosome--which encompasses 29 genes--that confers susceptibility to neurocognitive defects when deleted or duplicated. Overexpression of each human transcript in zebrafish embryos identified KCTD13 as the sole message capable of inducing the microcephaly phenotype associated with the 16p11.2 duplication, whereas suppression of the same locus yielded the macrocephalic phenotype associated with the 16p11.2 deletion, capturing the mirror phenotypes of humans. Analyses of zebrafish and mouse embryos suggest that microcephaly is caused by decreased proliferation of neuronal progenitors with concomitant increase in apoptosis in the developing brain, whereas macrocephaly arises by increased proliferation and no changes in apoptosis. A role for KCTD13 dosage changes is consistent with autism in both a recently reported family with a reduced 16p11.2 deletion and a subject reported here with a complex 16p11.2 rearrangement involving de novo structural alteration of KCTD13. Our data suggest that KCTD13 is a major driver for the neurodevelopmental phenotypes associated with the 16p11.2 CNV, reinforce the idea that one or a small number of transcripts within a CNV can underpin clinical phenotypes, and offer an efficient route to identifying dosage-sensitive loci.
Published: 2012

49. Genetic testing in patients with obesity

Author: Jacques S. Beckmann, F. Phan-Hug, and Sébastien Jacquemont
Subjects: Leptin, Endocrinology, Diabetes and Metabolism, Genome-wide association study, Biology, Bioinformatics, Endocrinology, Twins, Dizygotic, medicine, Humans, Cilia, Genetic Testing, Obesity, Genetic testing, Genetic association, Genetics, Comparative Genomic Hybridization, medicine.diagnostic_test, Learning Disabilities, Twins, Monozygotic, Heritability, medicine.disease, Twin study, Melanocortins, Identification (biology), Prader-Willi Syndrome, Hypothalamic Diseases, Genome-Wide Association Study, Comparative genomic hybridization
Abstract: The obesity epidemic is associated with the recent availability of highly palatable and inexpensive caloric food as well as important changes in lifestyle. Genetic factors, however, play a key role in regulating energy balance and numerous twin studies have estimated the BMI heritability between 40 and 70%. While common variants, identified through genome-wide association studies (GWAS) point toward new pathways, their effect size are too low to be of any use in the clinic. This review therefore concentrates on genes and genomic regions associated with very high risks of human obesity. Although there are no consensus guidelines, we review how the knowledge on these "causal factors" can be translated into the clinic for diagnostic purposes. We propose genetic workups guided by clinical manifestations in patients with severe early-onset obesity. While etiological diagnoses are unequivocal in a minority of patients, new genomic tools such as Comparative Genomic Hybridization (CGH) array, have allowed the identification of novel "causal" loci and next-generation sequencing brings the promise of accelerated pace for discoveries relevant to clinical practice.
Published: 2012

50. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

Author: Laurent Pasquier, Anne V. Snow, David T. Miller, Louise Harewood, Christina Triantafallou, Timothy P.L. Roberts, Leighton B. Hinkley, Zili Chu, Louis Vallée, Alyss Lian Cavanagh, Evica Rajcan-Separovic, Patricia Blanchet, Fiona Miller, Robin P. Goin-Kochel, Beau Reilly, Bettina Cerban, Vanessa Siffredi, Bridget A. Fernandez, Roger Vaughan, Brianna M. Paul, Fanny Morice-Picard, Elisabeth Flori, Dominique Campion, Gérard Didelot, Anne Philippe, Christa Lese Martin, Srikantan S. Nagarajan, Joris Andrieux, Jacques Puechberty, Marie Pierre Cordier, Jill V. Hunter, Ellen van Binsbergen, Catherine Vincent-Delorme, Vivek Swarnakar, Jean Marie Cuisset, Monica Proud, Patrick Callier, Bert B.A. de Vries, Jeffrey I. Berman, Sarah J. Spence, Alexandra Bowe, Wendy K. Chung, Katy Ankenman, Katherine Hines, Sarah E. Gobuty, Philippe Jonveaux, Lisa Blaskey, Alice Goldenberg, Sylvie Jaillard, Alessandra Renieri, Anne M. Maillard, Tracy Luks, Lee Anne Green Snyder, Elliott H. Sherr, Sarah Y. Khan, Fabienne Prieur, Simon A. Zwolinski, Andres Metspalu, Ghislaine Plessis, Jean Chiesa, Rita J. Jeremy, Valérie Malan, Michèle Mathieu-Dramard, Loyse Hippolyte, Bethanny Smith-Packard, Andrea M. Paal, Bénédicte Duban Bedu, Claudine Rieubland, Jordan Burko, Sylvie Joriot, Philippe Conus, Dominique Bonneau, Benoit Arveiler, Nicole de Leeuw, Allison G. Dempsey, John E. Spiro, Julia Wenegrat, Bertrand Isidor, Cédric Le Caignec, Kyle J. Steinman, Bruno Delobel, Ashlie Llorens, Jacques S. Beckmann, Kelly Johnson, Sean Ackerman, Polina Bukshpun, Silvia Garza, Alexandre Reymond, Damien Sanlaville, Ellen Hanson, Martine Doco-Fenzy, Jacques Thonney, Mari Wakahiro, Juliane Hoyer, Jacqueline Vigneron, Katrin Õunap, Arthur L. Beaudet, Mandy Barker, Nicole Visyak, Sonia Bouquillon, W. Andrew Faucett, Raphael Bernier, Sudha Kilaru Kessler, Audrey Lynn Bibb, Dennis Shaw, R. Frank Kooy, Suzanne M E Lewis, Anna L. Laakman, Nicholas J. Pojman, Hubert Journel, Laura Bernardini, Arianne Stevens, Julia P. Owen, Rebecca Mc Nally Keehn, Stéphanie Selmoni, Sébastien Lebon, Aurélien Macé, Bruno Leheup, Saba Qasmieh, Zoltán Kutalik, Anita Rauch, Yiping Shen, Elysa J. Marco, Nathalie Van der Aa, Carina Ferrari, Noam D. Beckmann, Delphine Héron, Jennifer Tjernage, Benjamin Aaronson, Albert David, Marie Pierre Lemaitre, Muriel Holder, Eve Õiglane-Shlik, Anneke T. Vulto-van Silfhout, Flore Zufferey, Constance Atwell, Marta Benedetti, Ellen Grant, Jenna Elgin, Patricia Z. Page, Caroline Rooryck, Randy L. Buckner, Qixuan Chen, Laurence Faivre, Sébastien Jacquemont, Kerri P. Nowell, Florence Fellmann, Disciglio Vittoria, Katharina Magdalena Rötzer, Hana Lee, Alastair J. Martin, Marion Greenup, David H. Ledbetter, Katrin Männik, Morgan W. Lasala, Jennifer Gerdts, Hanalore Alupay, Florence Petit, Elizabeth Aylward, Gerald D. Fischbach, Mafalda Mucciolo, Maxwell Cheong, Gabriela Marzano, Frédérique Béna, Danielle Martinet, Timothy J. Moss, Odile Boute, Jennifer Olson, Marco Belfiore, Christina Fagerberg, Corby L. Dale, Robert M. Witwicki, Yolanda L. Evans, Melissa B. Ramocki, Marie-Claude Addor, Christèle Dubourg, Mariken Ruiter, Tuhin K. Sinha, Mieke M. van Haelst, Alan Packer, Kathleen E. McGovern, Christie M. Brewton, Stephen M. Kanne, Richard I. Fisher, Tracey Ward, Sophie Dupuis-Girod, Pratik Mukherjee, Simons VIP Consortium, 16p11.2 European Consortium, Addor, MC., Arveiler, B., Belfiore, M., Bena, F., Bernardini, L., Blanchet, P., Bonneau, D., Boute, O., Callier, P., Campion, D., Chiesa, J., Cordier, MP., Cuisset, JM., David, A., de Leeuw, N., de Vries, B., Didelot, G., Doco-Fenzy, M., Bedu, BD., Dubourg, C., Dupuis-Girod, S., Fagerberg, CR., Faivre, L., Fellmann, F., Fernandez, BA., Fisher, R., Flori, E., Goldenberg, A., Heron, D., Holder, M., Hoyer, J., Isidor, B., Jaillard, S., Jonveaux, P., Joriot, S., Journel, H., Kooy, F., le Caignec, C., Leheup, B., Lemaitre, MP., Lewis, S., Malan, V., Mathieu-Dramard, M., Metspalu, A., Morice-Picard, F., Mucciolo, M., Oiglane-Shlik, E., Ounap, K., Pasquier, L., Petit, F., Philippe, A., Plessis, G., Prieur, F., Puechberty, J., Rajcan-Separovic, E., Rauch, A., Renieri, A., Rieubland, C., Rooryck, C., Rötzer, KM., Ruiter, M., Sanlaville, D., Selmoni, S., Shen, Y., Siffredi, V., Thonney, J., Vallée, L., van Binsbergen, E., Van der Aa, N., van Haelst MM., Vigneron, J., Vincent-Delorme, C., Vittoria, D., Vulto-van Silfhout AT., Witwicki, RM., Zwolinski, SA., Bowe, A., Beaudet, AL., Brewton, CM., Chu, Z., Dempsey, AG., Evans, YL., Garza, S., Kanne, SM., Laakman, AL., Lasala, MW., Llorens, AV., Marzano, G., Moss, TJ., Nowell, KP., Proud, MB., Chen, Q., Vaughan, R., Berman, J., Blaskey, L., Hines, K., Kessler, S., Khan, SY., Qasmieh, S., Bibb, AL., Paal, AM., Page, PZ., Smith-Packard, B., Buckner, R., Burko, J., Cavanagh, AL., Cerban, B., Snow, AV., Snyder, LG., Keehn, RM., Miller, DT., Miller, FK., Olson, JE., Triantafallou, C., Visyak, N., Atwell, C., Benedetti, M., Fischbach, GD., Greenup, M., Packer, A., Bukshpun, P., Cheong, M., Dale, C., Gobuty, SE., Hinkley, L., Jeremy, RJ., Lee, H., Luks, TL., Marco, EJ., Martin, AJ., McGovern, KE., Nagarajan, SS., Owen, J., Paul, BM., Pojman, NJ., Sinha, T., Swarnakar, V., Wakahiro, M., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Elgin, J., Gerdts, J., Johnson, K., Reilly, B., Shaw, D., Stevens, A., Ward, T., Wenegrat, J., Other departments, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), CHU Pontchaillou [Rennes], Department of Medical Genetics, Université de Lausanne (UNIL), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Texas Children's Hospital [Houston, USA], Department of pediatrics, Primary palliative Care Research Group, Community Health Sciences, General Practice Section, University of Edinburgh, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Developmental Brain and Behaviour Unit, University of Southampton, Institute of Molecular and Cell Biology, University of Tartu, Department of Human Genetics, UCLA, University of California [Los Angeles] (UCLA), University of California-University of California-Semel Institute, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Lausanne = University of Lausanne (UNIL), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), University of California (UC)-University of California (UC)-Semel Institute, 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 ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Kooy, Frank
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Heterozygote, Adolescent, [SDV]Life Sciences [q-bio], Developmental Disabilities, Biology, Body Mass Index, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Gene Order, Genetics, medicine, Humans, Copy-number variation, Clinical genetics, Obesity, Young adult, Child, Genetics (clinical), 030304 developmental biology, Child Development Disorders, Pervasive/diagnosis, Child Development Disorders, Pervasive/genetics, Chromosome Deletion, Chromosomes, Human, Pair 16, Developmental Disabilities/diagnosis, Developmental Disabilities/genetics, Female, Intelligence Tests, Phenotype, Syndrome, 2. Zero hunger, Psychiatry, 0303 health sciences, Intelligence quotient, Neuropsychology, Complex traits, medicine.disease, Comorbidity, 3. Good health, Autism spectrum disorder, Child Development Disorders, Pervasive, Autism, Medical genetics, Human medicine, Copy-Number Variation, 030217 neurology & neurosurgery
Abstract: Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.
Published: 2012

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