Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.

Basic Helix-Loop-Helix Transcription Factors / genetics CCCTC-Binding Factor / genetics Case-Control Studies Cohort Studies DNA Mutational Analysis DNA-Binding Proteins / genetics Female Genetic Association Studies Genetic Predisposition to Disease Heterogeneous-Nuclear Ribonucleoprotein U / genetics High-Throughput Nucleotide Sequencing Humans KCNQ3 Potassium Channel / genetics Male Mutation Neurodevelopmental Disorders / genetics RNA-Binding Proteins / genetics Repressor Proteins / genetics Transcription Factors / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
01 10 2020
Historique:
received: 09 04 2020
accepted: 04 09 2020
entrez: 2 10 2020
pubmed: 3 10 2020
medline: 21 10 2020
Statut: epublish

Résumé

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

Identifiants

DOI: 10.1038/s41467-020-18723-y PMID: 33004838 PMC: PMC7530681
pubmed: 33004838
doi: 10.1038/s41467-020-18723-y
pii: 10.1038/s41467-020-18723-y
pmc: PMC7530681
doi:

Substances chimiques

Basic Helix-Loop-Helix Transcription Factors 0
CCCTC-Binding Factor 0
CTCF protein, human 0
DNA-Binding Proteins 0
HNRNPU protein, human 0
Heterogeneous-Nuclear Ribonucleoprotein U 0
KCNQ3 Potassium Channel 0
KCNQ3 protein, human 0
LEO1 protein, human 0
RNA-Binding Proteins 0
Repressor Proteins 0
SPEN protein, human 0
Transcription Factors 0
ZBTB18 protein, human 0
TCF12 protein, human 142661-93-6

Types de publication

Journal Article Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

4932

Subventions

Organisme : NIMH NIH HHS
ID : R01 MH110558
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD103524
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG000035
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH109912
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH101221
Pays : United States

Investigateurs

John Acampado (J)
Andrea J Ace (AJ)
Alpha Amatya (A)
Irina Astrovskaya (I)
Asif Bashar (A)
Elizabeth Brooks (E)
Martin E Butler (ME)
Lindsey A Cartner (LA)
Wubin Chin (W)
Wendy K Chung (WK)
Amy M Daniels (AM)
Pamela Feliciano (P)
Chris Fleisch (C)
Swami Ganesan (S)
William Jensen (W)
Alex E Lash (AE)
Richard Marini (R)
Vincent J Myers (VJ)
Eirene O'Connor (E)
Chris Rigby (C)
Beverly E Robertson (BE)
Neelay Shah (N)
Swapnil Shah (S)
Emily Singer (E)
LeeAnne G Snyder (LG)
Alexandra N Stephens (AN)
Jennifer Tjernagel (J)
Brianna M Vernoia (BM)
Natalia Volfovsky (N)
Loran Casey White (LC)
Alexander Hsieh (A)
Yufeng Shen (Y)
Xueya Zhou (X)
Tychele N Turner (TN)
Ethan Bahl (E)
Taylor R Thomas (TR)
Leo Brueggeman (L)
Tanner Koomar (T)
Jacob J Michaelson (JJ)
Brian J O'Roak (BJ)
Rebecca A Barnard (RA)
Richard A Gibbs (RA)
Donna Muzny (D)
Aniko Sabo (A)
Kelli L Baalman Ahmed (KLB)
Evan E Eichler (EE)
Matthew Siegel (M)
Leonard Abbeduto (L)
David G Amaral (DG)
Brittani A Hilscher (BA)
Deana Li (D)
Kaitlin Smith (K)
Samantha Thompson (S)
Charles Albright (C)
Eric M Butter (EM)
Sara Eldred (S)
Nathan Hanna (N)
Mark Jones (M)
Daniel Lee Coury (DL)
Jessica Scherr (J)
Taylor Pifher (T)
Erin Roby (E)
Brandy Dennis (B)
Lorrin Higgins (L)
Melissa Brown (M)
Michael Alessandri (M)
Anibal Gutierrez (A)
Melissa N Hale (MN)
Lynette M Herbert (LM)
Hoa Lam Schneider (HL)
Giancarla David (G)
Robert D Annett (RD)
Dustin E Sarver (DE)
Ivette Arriaga (I)
Alexies Camba (A)
Amanda C Gulsrud (AC)
Monica Haley (M)
James T McCracken (JT)
Sophia Sandhu (S)
Maira Tafolla (M)
Wha S Yang (WS)
Laura A Carpenter (LA)
Catherine C Bradley (CC)
Frampton Gwynette (F)
Patricia Manning (P)
Rebecca Shaffer (R)
Carrie Thomas (C)
Raphael A Bernier (RA)
Emily A Fox (EA)
Jennifer A Gerdts (JA)
Micah Pepper (M)
Theodore Ho (T)
Daniel Cho (D)
Joseph Piven (J)
Holly Lechniak (H)
Latha V Soorya (LV)
Rachel Gordon (R)
Allison Wainer (A)
Lisa Yeh (L)
Cesar Ochoa-Lubinoff (C)
Nicole Russo (N)
Elizabeth Berry-Kravis (E)
Stephanie Booker (S)
Craig A Erickson (CA)
Lisa M Prock (LM)
Katherine G Pawlowski (KG)
Emily T Matthews (ET)
Stephanie J Brewster (SJ)
Margaret A Hojlo (MA)
Evi Abada (E)
Elena Lamarche (E)
Tianyun Wang (T)
Shwetha C Murali (SC)
William T Harvey (WT)
Hannah E Kaplan (HE)
Karen L Pierce (KL)
Lindsey DeMarco (L)
Susannah Horner (S)
Juhi Pandey (J)
Samantha Plate (S)
Mustafa Sahin (M)
Katherine D Riley (KD)
Erin Carmody (E)
Julia Constantini (J)
Amy Esler (A)
Ali Fatemi (A)
Hanna Hutter (H)
Rebecca J Landa (RJ)
Alexander P McKenzie (AP)
Jason Neely (J)
Vini Singh (V)
Bonnie Van Metre (B)
Ericka L Wodka (EL)
Eric J Fombonne (EJ)
Lark Y Huang-Storms (LY)
Lillian D Pacheco (LD)
Sarah A Mastel (SA)
Leigh A Coppola (LA)
Sunday Francis (S)
Andrea Jarrett (A)
Suma Jacob (S)
Natasha Lillie (N)
Jaclyn Gunderson (J)
Dalia Istephanous (D)
Laura Simon (L)
Ori Wasserberg (O)
Angela L Rachubinski (AL)
Cordelia R Rosenberg (CR)
Stephen M Kanne (SM)
Amanda D Shocklee (AD)
Nicole Takahashi (N)
Shelby L Bridwell (SL)
Rebecca L Klimczac (RL)
Melissa A Mahurin (MA)
Hannah E Cotrell (HE)
Cortaiga A Grant (CA)
Samantha G Hunter (SG)
Christa Lese Martin (CL)
Cora M Taylor (CM)
Lauren K Walsh (LK)
Katherine A Dent (KA)
Andrew Mason (A)
Anthony Sziklay (A)
Christopher J Smith (CJ)

Commentaires et corrections

Type : ErratumIn

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Auteurs

Tianyun Wang (T)

Department of Genome Sciences, University of Washington, Seattle, WA, USA.
ORCID: 0000-0002-5179-087X

Kendra Hoekzema (K)

Department of Genome Sciences, University of Washington, Seattle, WA, USA.

Davide Vecchio (D)

Rare Disease and Medical Genetics, Academic Department of Pediatrics, Bambino Gesù Children's Hospital, Rome, Italy.
Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Rome, Italy.
ORCID: 0000-0003-2907-3206

Huidan Wu (H)

Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.

Arvis Sulovari (A)

Department of Genome Sciences, University of Washington, Seattle, WA, USA.
ORCID: 0000-0003-4354-9020

Bradley P Coe (BP)

Department of Genome Sciences, University of Washington, Seattle, WA, USA.

Madelyn A Gillentine (MA)

Department of Genome Sciences, University of Washington, Seattle, WA, USA.
ORCID: 0000-0002-8989-2214

Amy B Wilfert (AB)

Department of Genome Sciences, University of Washington, Seattle, WA, USA.

Luis A Perez-Jurado (LA)

Paediatric and Reproductive Genetics unit, Women's and Children's Hospital, Adelaide, SA, Australia.
South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM) and CIBERER, Barcelona, Spain.

Malin Kvarnung (M)

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Yoeri Sleyp (Y)

Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium.

Rachel K Earl (RK)

Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.

Jill A Rosenfeld (JA)

Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Baylor Genetics, Houston, TX, USA.
ORCID: 0000-0001-5664-7987

Madeleine R Geisheker (MR)

Department of Genome Sciences, University of Washington, Seattle, WA, USA.
ORCID: 0000-0002-4166-3236

Lin Han (L)

Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.

Bing Du (B)

Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.

Chris Barnett (C)

Paediatric and Reproductive Genetics unit, Women's and Children's Hospital, Adelaide, SA, Australia.
Adelaide Medical School and the Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia.

Elizabeth Thompson (E)

Paediatric and Reproductive Genetics unit, Women's and Children's Hospital, Adelaide, SA, Australia.

Marie Shaw (M)

Adelaide Medical School and the Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia.

Renee Carroll (R)

Adelaide Medical School and the Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia.

Kathryn Friend (K)

Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.

Rachael Catford (R)

Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.

Elizabeth E Palmer (EE)

Genetics of Learning Disability Service, Hunter New England Health Service, Waratah, NSW, Australia.
School of Women's and Children's Health, University of New South Wales, Randwick, NSW, Australia.

Xiaobing Zou (X)

Children Development Behavior Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.

Jianjun Ou (J)

Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, China.

Honghui Li (H)

Key Laboratory of Developmental Disorders in Children, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, China.

Hui Guo (H)

Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
ORCID: 0000-0002-1570-2545

Jennifer Gerdts (J)

Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.

Emanuela Avola (E)

Oasi Research Institute-IRCCS, Troina, Italy.

Giuseppe Calabrese (G)

Oasi Research Institute-IRCCS, Troina, Italy.

Maurizio Elia (M)

Oasi Research Institute-IRCCS, Troina, Italy.

Donatella Greco (D)

Oasi Research Institute-IRCCS, Troina, Italy.

Anna Lindstrand (A)

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
ORCID: 0000-0003-0806-5602

Ann Nordgren (A)

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
ORCID: 0000-0003-3285-4281

Britt-Marie Anderlid (BM)

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Geert Vandeweyer (G)

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.

Anke Van Dijck (A)

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
ORCID: 0000-0002-6713-2943

Nathalie Van der Aa (N)

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.

Brooke McKenna (B)

Department of Psychology, Emory University, Atlanta, GA, USA.

Miroslava Hancarova (M)

Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.

Sarka Bendova (S)

Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.

Marketa Havlovicova (M)

Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.

Giovanni Malerba (G)

Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Bernardo Dalla Bernardina (BD)

Child Neuropsychiatry Unit, AOUI, Verona, Italy.

Pierandrea Muglia (P)

UCB Pharma, Bruxelles, Belgium.

Arie van Haeringen (A)

Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, Netherlands.

Mariette J V Hoffer (MJV)

Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, Netherlands.
ORCID: 0000-0002-1812-7670

Barbara Franke (B)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands.
Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands.
ORCID: 0000-0003-4375-6572

Gerarda Cappuccio (G)

Department of Translational Medicine, Federico II University, Naples, Italy.
Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.

Martin Delatycki (M)

Murdoch Children's Research Institute, Melbourne, Australia.

Paul J Lockhart (PJ)

Murdoch Children's Research Institute, Melbourne, Australia.
Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia.
ORCID: 0000-0003-2531-8413

Melanie A Manning (MA)

Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA, USA.
Department of Pathology, Stanford University, Stanford, CA, USA.

Pengfei Liu (P)

Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Baylor Genetics, Houston, TX, USA.
ORCID: 0000-0002-4177-709X

Ingrid E Scheffer (IE)

Murdoch Children's Research Institute, Melbourne, Australia.
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC, Australia.
Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.
The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.

Nicola Brunetti-Pierri (N)

Department of Translational Medicine, Federico II University, Naples, Italy.
Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
ORCID: 0000-0002-6895-8819

Nanda Rommelse (N)

Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands.
Karakter Child and Adolescent Psychiatry Center, Nijmegen, Netherlands.

David G Amaral (DG)

Department of Psychiatry and Behavioral Sciences and the MIND Institute, University of California, Davis, Sacramento, CA, USA.

Gijs W E Santen (GWE)

Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, Netherlands.

Elisabetta Trabetti (E)

Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Zdeněk Sedláček (Z)

Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.

Jacob J Michaelson (JJ)

Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
ORCID: 0000-0001-9713-0992

Karen Pierce (K)

Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, CA, USA.

Eric Courchesne (E)

Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, CA, USA.
ORCID: 0000-0002-3772-5799

R Frank Kooy (RF)

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
ORCID: 0000-0003-2024-0485

Magnus Nordenskjöld (M)

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Corrado Romano (C)

Oasi Research Institute-IRCCS, Troina, Italy.
ORCID: 0000-0003-1049-0683

Hilde Peeters (H)

Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium.

Raphael A Bernier (RA)

Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.

Jozef Gecz (J)

South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
Adelaide Medical School and the Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia.
Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
ORCID: 0000-0002-7884-6861

Kun Xia (K)

Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), Chinese Academy of Sciences, Shanghai, China.
ORCID: 0000-0001-8090-6002

Evan E Eichler (EE)

Department of Genome Sciences, University of Washington, Seattle, WA, USA. eee@gs.washington.edu.
Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. eee@gs.washington.edu.
ORCID: 0000-0002-8246-4014

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique hélice-boucle-hélice › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines de répression › Facteur de liaison à la séquence CCCTC › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études cas-témoins › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Analyse de mutations d'ADN › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Études d'associations génétiques › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines de liaison à l'ARN › Protéines à motif de reconnaissance de l'ARN › Ribonucléoprotéines nucléaires hétérogènes › Ribonucléoprotéine nucléaire hétérogène U › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Séquençage nucléotidique à haut débit › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Canaux ioniques › Canaux potassiques › Canaux potassiques voltage-dépendants › Canaux potassiques rectifiants retardés › Canaux potassiques KNCQ › Canal potassique KCNQ3 › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines de liaison à l'ARN › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines de répression › Large-scale targeted sequencing identifies...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Large-scale targeted sequencing identifies...