title: Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism.
abstract: The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features, TRIP12 mutation carriers showed intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene and clinically review four previously published cases. The TRIP12 mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability [intelligence quotient (IQ) 76 in one individual], ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11 TRIP12 mutation-positive individuals and thereby expand the clinical spectrum of the TRIP12 gene in non-syndromic intellectual disability with or without ASD.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany. nuria.braemswig@uni-due.de.
authors.forename: Nuria C
authors.identifier: 0000-0002-3367-586X
authors.initials: NC
authors.lastname: Bramswig
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.|Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lüdecke
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Pettersson
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Albrecht
authors.affiliation: Department of Psychiatry, University of Washington, Seattle, WA, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Bernier
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Cremer
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Eichler
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.|Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Falkenstein
authors.affiliation: Department of Psychiatry, University of Washington, Seattle, WA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gerdts
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Jansen
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kuechler
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Kvarnung
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Lindstrand
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.|Science for Life Laboratory, Karolinska Institutet Science Park, Solna, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Nilsson
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Nordgren
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: R
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: L
authors.initials: L
authors.lastname: Spruijt
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: H M
authors.initials: HM
authors.lastname: Surowy
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: B B A
authors.initials: BB
authors.lastname: de Vries
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Engels
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: T M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.|Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Wieczorek
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D007621:Karyotyping; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D059748:Proteolysis; D012326:RNA Splicing; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C530813:TRIP12 protein, human; D044767:Ubiquitin-Protein Ligases