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

Padhi, Evin M.; Hayeck, Tristan J.; Cheng, Zhang; Chatterjee, Sumantra; Mannion, Brandon J.; Byrska-Bishop, Marta; Willems, Marjolaine; Pinson, Lucile; Redon, Sylvia; Benech, Caroline; Uguen, Kevin; Audebert-Bellanger, Séverine; Le Marechal, Cédric; Férec, Claude; Efthymiou, Stephanie; Rahman, Fatima; Maqbool, Shazia; Maroofian, Reza; Houlden, Henry; Musunuri, Rajeeva; Narzisi, Giuseppe; Abhyankar, Avinash; Hunter, Riana D.; Akiyama, Jennifer; Fries, Lauren E.; Ng, Jeffrey K.; Mehinovic, Elvisa; Stong, Nick; Allen, Andrew S.; Dickel, Diane E.; Bernier, Raphael A.; Gorkin, David U.; Pennacchio, Len A.; Zody, Michael C.; Turner, Tychele N.

doi:10.1186/s40246-021-00342-3

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

Journal Article · 12 July 2021 · Human Genomics

DOI: https://doi.org/10.1186/s40246-021-00342-3 · OSTI ID:1807726

Padhi, Evin M.; Hayeck, Tristan J.; Cheng, Zhang; Chatterjee, Sumantra; Mannion, Brandon J.; Byrska-Bishop, Marta; Willems, Marjolaine; Pinson, Lucile; Redon, Sylvia; Benech, Caroline; Uguen, Kevin; Audebert-Bellanger, Séverine; Le Marechal, Cédric; Férec, Claude; Efthymiou, Stephanie; Rahman, Fatima; Maqbool, Shazia; Maroofian, Reza; Houlden, Henry; Musunuri, Rajeeva more »

Abstract Background Previous 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. Results We 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. Conclusions In 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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE; USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1807726

Journal Information:: Human Genomics, Journal Name: Human Genomics Journal Issue: 1 Vol. 15; ISSN 1479-7364

Publisher:: Springer Science + Business MediaCopyright Statement

Country of Publication:: United Kingdom

Language:: English

References (65)

The Heritability of Autism Spectrum Disorder Sandin, Sven; Lichtenstein, Paul; Kuja-Halkola, Ralf JAMA, Vol. 318, Issue 12 https://doi.org/10.1001/jama.2017.12141	journal	September 2017
Interpreting de novo Variation in Human Disease Using denovolyzeR Ware, James S.; Samocha, Kaitlin E.; Homsy, Jason Current Protocols in Human Genetics, Vol. 87, Issue 1 https://doi.org/10.1002/0471142905.hg0725s87	journal	October 2015
MuPIT interactive: webserver for mapping variant positions to annotated, interactive 3D structures Niknafs, Noushin; Kim, Dewey; Kim, RyangGuk Human Genetics, Vol. 132, Issue 11 https://doi.org/10.1007/s00439-013-1325-0	journal	June 2013
Refinement and Discovery of New Hotspots of Copy-Number Variation Associated with Autism Spectrum Disorder Girirajan, Santhosh; Dennis, Megan Y.; Baker, Carl The American Journal of Human Genetics, Vol. 92, Issue 2 https://doi.org/10.1016/j.ajhg.2012.12.016	journal	February 2013
Incorporating Functional Information in Tests of Excess De Novo Mutational Load Jiang, Yu; Han, Yujun; Petrovski, Slavé The American Journal of Human Genetics, Vol. 97, Issue 2 https://doi.org/10.1016/j.ajhg.2015.06.013	journal	August 2015
Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA Turner, Tychele N.; Hormozdiari, Fereydoun; Duyzend, Michael H. The American Journal of Human Genetics, Vol. 98, Issue 1 https://doi.org/10.1016/j.ajhg.2015.11.023	journal	January 2016
Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism Harms, Frederike Leonie; Girisha, Katta M.; Hardigan, Andrew A. The American Journal of Human Genetics, Vol. 100, Issue 1 https://doi.org/10.1016/j.ajhg.2016.11.012	journal	January 2017
A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3 Chao, Hsiao-Tuan; Davids, Mariska; Burke, Elizabeth The American Journal of Human Genetics, Vol. 100, Issue 1 https://doi.org/10.1016/j.ajhg.2016.11.018	journal	January 2017
De Novo Mutations in EBF3 Cause a Neurodevelopmental Syndrome Sleven, Hannah; Welsh, Seth J.; Yu, Jing The American Journal of Human Genetics, Vol. 100, Issue 1 https://doi.org/10.1016/j.ajhg.2016.11.020	journal	January 2017
Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders Turner, Tychele N.; Wilfert, Amy B.; Bakken, Trygve E. The American Journal of Human Genetics, Vol. 105, Issue 6 https://doi.org/10.1016/j.ajhg.2019.11.003	journal	December 2019
Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development Bernier, Raphael; Golzio, Christelle; Xiong, Bo Cell, Vol. 158, Issue 2 https://doi.org/10.1016/j.cell.2014.06.017	journal	July 2014
Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease Chatterjee, Sumantra; Kapoor, Ashish; Akiyama, Jennifer A. Cell, Vol. 167, Issue 2 https://doi.org/10.1016/j.cell.2016.09.005	journal	October 2016
Genomic Patterns of De Novo Mutation in Simplex Autism Turner, Tychele N.; Coe, Bradley P.; Dickel, Diane E. Cell, Vol. 171, Issue 3 https://doi.org/10.1016/j.cell.2017.08.047	journal	October 2017
Multiscale 3D Genome Rewiring during Mouse Neural Development Bonev, Boyan; Mendelson Cohen, Netta; Szabo, Quentin Cell, Vol. 171, Issue 3 https://doi.org/10.1016/j.cell.2017.09.043	journal	October 2017
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom, F. Kyle; Kosmicki, Jack A.; Wang, Jiebiao Cell, Vol. 180, Issue 3 https://doi.org/10.1016/j.cell.2019.12.036	journal	February 2020
Comprehensive In Vivo Interrogation Reveals Phenotypic Impact of Human Enhancer Variants Kvon, Evgeny Z.; Zhu, Yiwen; Kelman, Guy Cell, Vol. 180, Issue 6 https://doi.org/10.1016/j.cell.2020.02.031	journal	March 2020
A Chromatin Accessibility Atlas of the Developing Human Telencephalon Markenscoff-Papadimitriou, Eirene; Whalen, Sean; Przytycki, Pawel Cell, Vol. 182, Issue 3 https://doi.org/10.1016/j.cell.2020.06.002	journal	August 2020
Juicer Provides a One-Click System for Analyzing Loop-Resolution Hi-C Experiments Durand, Neva C.; Shamim, Muhammad S.; Machol, Ido Cell Systems, Vol. 3, Issue 1 https://doi.org/10.1016/j.cels.2016.07.002	journal	July 2016
The Simons Simplex Collection: A Resource for Identification of Autism Genetic Risk Factors Fischbach, Gerald D.; Lord, Catherine Neuron, Vol. 68, Issue 2 https://doi.org/10.1016/j.neuron.2010.10.006	journal	October 2010
Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism Sanders, Stephan J.; Ercan-Sencicek, A. Gulhan; Hus, Vanessa Neuron, Vol. 70, Issue 5 https://doi.org/10.1016/j.neuron.2011.05.002	journal	June 2011
Rare De Novo and Transmitted Copy-Number Variation in Autistic Spectrum Disorders Levy, Dan; Ronemus, Michael; Yamrom, Boris Neuron, Vol. 70, Issue 5 https://doi.org/10.1016/j.neuron.2011.05.015	journal	June 2011
De Novo Gene Disruptions in Children on the Autistic Spectrum Iossifov, Ivan; Ronemus, Michael; Levy, Dan Neuron, Vol. 74, Issue 2 https://doi.org/10.1016/j.neuron.2012.04.009	journal	April 2012
Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders, Stephan J.; He, Xin; Willsey, A. Jeremy Neuron, Vol. 87, Issue 6 https://doi.org/10.1016/j.neuron.2015.09.016	journal	September 2015
DOG 1.0: illustrator of protein domain structures Ren, Jian; Wen, Longping; Gao, Xinjiao Cell Research, Vol. 19, Issue 2 https://doi.org/10.1038/cr.2009.6	journal	January 2009
Finding the missing heritability of complex diseases Manolio, Teri A.; Collins, Francis S.; Cox, Nancy J. Nature, Vol. 461, Issue 7265 https://doi.org/10.1038/nature08494	journal	October 2009
De novo mutations revealed by whole-exome sequencing are strongly associated with autism Sanders, Stephan J.; Murtha, Michael T.; Gupta, Abha R. Nature, Vol. 485, Issue 7397 https://doi.org/10.1038/nature10945	journal	April 2012
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations O’Roak, Brian J.; Vives, Laura; Girirajan, Santhosh Nature, Vol. 485, Issue 7397 https://doi.org/10.1038/nature10989	journal	April 2012
Patterns and rates of exonic de novo mutations in autism spectrum disorders Neale, Benjamin M.; Kou, Yan; Liu, Li Nature, Vol. 485, Issue 7397 https://doi.org/10.1038/nature11011	journal	April 2012
Topological domains in mammalian genomes identified by analysis of chromatin interactions Dixon, Jesse R.; Selvaraj, Siddarth; Yue, Feng Nature, Vol. 485, Issue 7398 https://doi.org/10.1038/nature11082	journal	April 2012
Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis, Silvia; He, Xin; Goldberg, Arthur P. Nature, Vol. 515, Issue 7526 https://doi.org/10.1038/nature13772	journal	October 2014
The contribution of de novo coding mutations to autism spectrum disorder Iossifov, Ivan; O’Roak, Brian J.; Sanders, Stephan J. Nature, Vol. 515, Issue 7526 https://doi.org/10.1038/nature13908	journal	October 2014
Chromosome conformation elucidates regulatory relationships in developing human brain Won, Hyejung; de la Torre-Ubieta, Luis; Stein, Jason L. Nature, Vol. 538, Issue 7626 https://doi.org/10.1038/nature19847	journal	October 2016
The Genotype-Tissue Expression (GTEx) project Lonsdale, John; Thomas, Jeffrey; Salvatore, Mike Nature Genetics, Vol. 45, Issue 6 https://doi.org/10.1038/ng.2653	journal	May 2013
Most genetic risk for autism resides with common variation Gaugler, Trent; Klei, Lambertus; Sanders, Stephan J. Nature Genetics, Vol. 46, Issue 8 https://doi.org/10.1038/ng.3039	journal	July 2014
Refining analyses of copy number variation identifies specific genes associated with developmental delay Coe, Bradley P.; Witherspoon, Kali; Rosenfeld, Jill A. Nature Genetics, Vol. 46, Issue 10 https://doi.org/10.1038/ng.3092	journal	September 2014
Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders Weiner, Daniel J.; Wigdor, Emilie M.; Ripke, Stephan Nature Genetics, Vol. 49, Issue 7 https://doi.org/10.1038/ng.3863	journal	May 2017
Genome partitioning of genetic variation for complex traits using common SNPs Yang, Jian; Manolio, Teri A.; Pasquale, Louis R. Nature Genetics, Vol. 43, Issue 6 https://doi.org/10.1038/ng.823	journal	May 2011
Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations O'Roak, Brian J.; Deriziotis, Pelagia; Lee, Choli Nature Genetics, Vol. 43, Issue 6 https://doi.org/10.1038/ng.835	journal	May 2011
A copy number variation morbidity map of developmental delay Cooper, Gregory M.; Coe, Bradley P.; Girirajan, Santhosh Nature Genetics, Vol. 43, Issue 9 https://doi.org/10.1038/ng.909	journal	August 2011
ChromHMM: automating chromatin-state discovery and characterization Ernst, Jason; Kellis, Manolis Nature Methods, Vol. 9, Issue 3 https://doi.org/10.1038/nmeth.1906	journal	February 2012
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources Huang, Da Wei; Sherman, Brad T.; Lempicki, Richard A. Nature Protocols, Vol. 4, Issue 1 https://doi.org/10.1038/nprot.2008.211	journal	December 2008
An atlas of dynamic chromatin landscapes in mouse fetal development Gorkin, David U.; Barozzi, Iros; Zhao, Yuan Nature, Vol. 583, Issue 7818 https://doi.org/10.1038/s41586-020-2093-3	journal	July 2020
A structural variation reference for medical and population genetics Collins, Ryan L.; Brand, Harrison; Karczewski, Konrad J. Nature, Vol. 581, Issue 7809 https://doi.org/10.1038/s41586-020-2287-8	journal	May 2020
The mutational constraint spectrum quantified from variation in 141,456 humans Karczewski, Konrad J.; Francioli, Laurent C.; Tiao, Grace Nature, Vol. 581, Issue 7809 https://doi.org/10.1038/s41586-020-2308-7	journal	May 2020
Expanded encyclopaedias of DNA elements in the human and mouse genomes Moore, Jill E.; Purcaro, Michael J.; Pratt, Henry E. Nature, Vol. 583, Issue 7818 https://doi.org/10.1038/s41586-020-2493-4	journal	July 2020
Evidence for 28 genetic disorders discovered by combining healthcare and research data Kaplanis, Joanna; Samocha, Kaitlin E.; Wiel, Laurens Nature, Vol. 586, Issue 7831 https://doi.org/10.1038/s41586-020-2832-5	journal	October 2020
Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity Coe, Bradley P.; Stessman, Holly A. F.; Sulovari, Arvis Nature Genetics, Vol. 51, Issue 1 https://doi.org/10.1038/s41588-018-0288-4	journal	December 2018
Identification of common genetic risk variants for autism spectrum disorder Grove, Jakob; Ripke, Stephan; Als, Thomas D. Nature Genetics, Vol. 51, Issue 3 https://doi.org/10.1038/s41588-019-0344-8	journal	February 2019
BEDTools: a flexible suite of utilities for comparing genomic features Quinlan, Aaron R.; Hall, Ira M. Bioinformatics, Vol. 26, Issue 6 https://doi.org/10.1093/bioinformatics/btq033	journal	January 2010
Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE Celestino-Soper, Patricia B. S.; Shaw, Chad A.; Sanders, Stephan J. Human Molecular Genetics, Vol. 20, Issue 22 https://doi.org/10.1093/hmg/ddr363	journal	August 2011
VISTA: computational tools for comparative genomics Frazer, K. A.; Pachter, L.; Poliakov, A. Nucleic Acids Research, Vol. 32, Issue Web Server https://doi.org/10.1093/nar/gkh458	journal	July 2004
VISTA Enhancer Browser--a database of tissue-specific human enhancers Visel, A.; Minovitsky, S.; Dubchak, I. Nucleic Acids Research, Vol. 35, Issue Database https://doi.org/10.1093/nar/gkl822	journal	January 2007
ENCODE data at the ENCODE portal Sloan, Cricket A.; Chan, Esther T.; Davidson, Jean M. Nucleic Acids Research, Vol. 44, Issue D1 https://doi.org/10.1093/nar/gkv1160	journal	November 2015
QBiC-Pred: quantitative predictions of transcription factor binding changes due to sequence variants Martin, Vincentius; Zhao, Jingkang; Afek, Ariel Nucleic Acids Research, Vol. 47, Issue W1 https://doi.org/10.1093/nar/gkz363	journal	May 2019
Detection of nonneutral substitution rates on mammalian phylogenies Pollard, K. S.; Hubisz, M. J.; Rosenbloom, K. R. Genome Research, Vol. 20, Issue 1 https://doi.org/10.1101/gr.097857.109	journal	October 2009
The discovery of integrated gene networks for autism and related disorders Hormozdiari, Fereydoun; Penn, Osnat; Borenstein, Elhanan Genome Research, Vol. 25, Issue 1 https://doi.org/10.1101/gr.178855.114	journal	November 2014
The Human Genome Browser at UCSC Kent, W. J.; Sugnet, C. W.; Furey, T. S. Genome Research, Vol. 12, Issue 6 https://doi.org/10.1101/gr.229102	journal	May 2002
Strong Association of De Novo Copy Number Mutations with Autism Sebat, J.; Lakshmi, B.; Malhotra, D. Science, Vol. 316, Issue 5823 https://doi.org/10.1126/science.1138659	journal	April 2007
Systematic Localization of Common Disease-Associated Variation in Regulatory DNA Maurano, M. T.; Humbert, R.; Rynes, E. Science, Vol. 337, Issue 6099 https://doi.org/10.1126/science.1222794	journal	September 2012
Evolutionary changes in promoter and enhancer activity during human corticogenesis Reilly, S. K.; Yin, J.; Ayoub, A. E. Science, Vol. 347, Issue 6226 https://doi.org/10.1126/science.1260943	journal	March 2015
Paternally inherited cis-regulatory structural variants are associated with autism Brandler, William M.; Antaki, Danny; Gujral, Madhusudan Science, Vol. 360, Issue 6386 https://doi.org/10.1126/science.aan2261	journal	April 2018
Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder An, Joon-Yong; Lin, Kevin; Zhu, Lingxue Science, Vol. 362, Issue 6420 https://doi.org/10.1126/science.aat6576	journal	December 2018
Exome-Scale Discovery of Hotspot Mutation Regions in Human Cancer Using 3D Protein Structure Tokheim, Collin; Bhattacharya, Rohit; Niknafs, Noushin Cancer Research, Vol. 76, Issue 13 https://doi.org/10.1158/0008-5472.CAN-15-3190	journal	April 2016
Clinical phenotype of ASD-associated DYRK1A haploinsufficiency Earl, Rachel K.; Turner, Tychele N.; Mefford, Heather C. Molecular Autism, Vol. 8, Issue 1 https://doi.org/10.1186/s13229-017-0173-5	journal	October 2017
Rapid, Paralog-Sensitive CNV Analysis of 2457 Human Genomes Using QuicK-mer2 Shen, Feichen; Kidd, Jeffrey M. Genes, Vol. 11, Issue 2 https://doi.org/10.3390/genes11020141	journal	January 2020

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
EBF3
autism
de novo
enhancer
gene regulatory network
genome
hs737
neurodevelopmental disorder
variant

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

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