Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism

Human Genomics

Kevin Uguen¹  Caroline Benech¹  Cédric Le Marechal¹  Claude Férec¹  Sylvia Redon¹  Zhang Cheng²  David U. Gorkin³  Sumantra Chatterjee⁴  Lauren E. Fries⁴  Andrew S. Allen⁵  Evin M. Padhi⁶  Jeffrey K. Ng⁶  Elvisa Mehinovic⁶  Tychele N. Turner⁶  Henry Houlden⁷  Stephanie Efthymiou⁷  Reza Maroofian⁷  Shazia Maqbool⁸  Tristan J. Hayeck⁹  Raphael A. Bernier^1,10  Fatima Rahman^1,11  Jennifer Akiyama^1,12  Riana D. Hunter^1,12  Brandon J. Mannion^1,12  Diane E. Dickel^1,12  Len A. Pennacchio^1,13  Nick Stong^1,14  Marta Byrska-Bishop^1,15  Avinash Abhyankar^1,15  Rajeeva Musunuri^1,15  Giuseppe Narzisi^1,15  Michael C. Zody^1,15  Séverine Audebert-Bellanger^1,16  Marjolaine Willems^1,17  Lucile Pinson^1,17 

[1] CHU Brest, Inserm, Univ Brest, EFS,UMR 1078, GGB, F-29200, Brest, France;Center for Epigenomics, University of California San Diego School of Medicine, 9500 Gilman Drive, 92093, La Jolla, CA, USA;Center for Epigenomics, University of California San Diego School of Medicine, 9500 Gilman Drive, 92093, La Jolla, CA, USA;Department of Biology, Emory University, 30322, Atlanta, GA, USA;Center for Human Genetics and Genomics, NYU School of Medicine, 10016, New York, NY, USA;Center for Statistical Genetics and Genomics, Duke University, 27708, Durham, NC, USA;Division of Integrative Genomics, Duke University, 27708, Durham, NC, USA;Department of Biostatistics and Bioinformatics, Duke University, 27708, Durham, NC, USA;Department of Genetics, Washington University School of Medicine, 4523 Clayton Avenue, Campus Box 8232, 63110, St. Louis, MO, USA;Department of Neuromuscular Disorders, UCL Institute of Neurology, Queen Square, WC1N 3BG, London, UK;Department of Neuromuscular Disorders, UCL Institute of Neurology, Queen Square, WC1N 3BG, London, UK;Development and Behavioral Pediatrics Department, Institute of Child Health and Children Hospital, Lahore, Pakistan;Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, 19104, Philadelphia, PA, USA;Department of Psychiatry and Behavioral Sciences, University of Washington, 98195, Seattle, WA, USA;Development and Behavioral Pediatrics Department, Institute of Child Health and Children Hospital, Lahore, Pakistan;Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, 94720, Berkeley, CA, USA;Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, 94720, Berkeley, CA, USA;U.S. Department of Energy Joint Genome Institute, 94598, Walnut Creek, CA, USA;Institute for Genomic Medicine, Columbia University, 10027, New York, NY, USA;New York Genome Center, 10013, New York, NY, USA;Service de Génétique Médicale, CHRU de Brest, Brest, France;University of Montpellier, département de Génétique, maladies rares médecine personnalisée, U 1298, CHU Montpellier, University of Montpellier, Montpellier, France;

关键词: Autism;    Neurodevelopmental disorder;    Enhancer;    Gene regulatory network;    EBF3;    hs737;    Genome;    Variant;    De novo;   

DOI  :  10.1186/s40246-021-00342-3

来源: Springer

【 摘 要 】

BackgroundPrevious research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737.ResultsWe adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10−3), and combined dataset (p = 1.1 × 10−4). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10−35, loss-of-function p = 2.26 × 10−13) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10−6, OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia.ConclusionsIn this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs.

【 授权许可】

CC BY