title: Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.
abstract: To identify candidate genes for intellectual disability, we performed a meta-analysis on 2,637 de novo mutations, identified from the exomes of 2,104 patient-parent trios. Statistical analyses identified 10 new candidate ID genes: DLG4, PPM1D, RAC1, SMAD6, SON, SOX5, SYNCRIP, TCF20, TLK2 and TRIP12. In addition, we show that these genes are intolerant to nonsynonymous variation and that mutations in these genes are associated with specific clinical ID phenotypes.
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Lelieveld
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Margot R F
authors.identifier: 0000-0002-6379-7147
authors.initials: MR
authors.lastname: Reijnders
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Helger G
authors.initials: HG
authors.lastname: Yntema
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Erik-Jan
authors.initials: EJ
authors.lastname: Kamsteeg
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: de Vries
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Marjolein H
authors.initials: MH
authors.lastname: Willemsen
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Katharina
authors.initials: K
authors.lastname: Löhner
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: Vreeburg
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Servi J C
authors.initials: SJ
authors.lastname: Stevens
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Ineke
authors.initials: I
authors.lastname: van der Burgt
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Ernie M H F
authors.initials: EM
authors.lastname: Bongers
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Alexander P A
authors.initials: AP
authors.lastname: Stegmann
authors.affiliation: Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Patrick
authors.identifier: 0000-0003-4059-0247
authors.initials: P
authors.lastname: Rump
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Tuula
authors.initials: T
authors.lastname: Rinne
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Marcel R
authors.initials: MR
authors.lastname: Nelen
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Christian
authors.identifier: 0000-0003-1693-9699
authors.initials: C
authors.lastname: Gilissen
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D000076122:Disks Large Homolog 4 Protein; D059472:Exome / Q000235:genetics; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D015778:Minor Histocompatibility Antigens / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics; D000071636:Protein Phosphatase 2C / Q000235:genetics; D055755:SOXD Transcription Factors / Q000235:genetics; D051905:Smad6 Protein / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000235:genetics
chemical_list: D002352:Carrier Proteins; C501444:DLG4 protein, human; D004268:DNA-Binding Proteins; D000076122:Disks Large Homolog 4 Protein; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; C107953:RAC1 protein, human; C497802:SMAD6 protein, human; C088203:SON protein, human; C490301:SOX5 protein, human; D055755:SOXD Transcription Factors; C425312:SYNCRIP protein, human; D051905:Smad6 Protein; C114750:TCF20 protein, human; D014157:Transcription Factors; C530813:TRIP12 protein, human; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C121377:protein kinase U; C000607458:PPM1D protein, human; D000071636:Protein Phosphatase 2C; D020830:rac1 GTP-Binding Protein