title: De novo nonsense and frameshift variants of TCF20 in individuals with intellectual disability and postnatal overgrowth.
abstract: Recently, germline variants of the transcriptional co-regulator gene TCF20 have been implicated in the aetiology of autism spectrum disorders (ASD). However, the knowledge about the associated clinical picture remains fragmentary. In this study, two individuals with de novo TCF20 sequence variants were identified in a cohort of 313 individuals with intellectual disability of unknown aetiology, which was analysed by whole exome sequencing using a child-parent trio design. Both detected variants - one nonsense and one frameshift variant - were truncating. A comprehensive clinical characterisation of the patients yielded mild intellectual disability, postnatal tall stature and macrocephaly, obesity and muscular hypotonia as common clinical signs while ASD was only present in one proband. The present report begins to establish the clinical picture of individuals with de novo nonsense and frameshift variants of TCF20 which includes features such as proportionate overgrowth and muscular hypotonia. Furthermore, intellectual disability/developmental delay seems to be fully penetrant amongst known individuals with de novo nonsense and frameshift variants of TCF20, whereas ASD is shown to be incompletely penetrant. The transcriptional co-regulator gene TCF20 is hereby added to the growing number of genes implicated in the aetiology of both ASD and intellectual disability. Furthermore, such de novo variants of TCF20 may represent a novel differential diagnosis in the overgrowth syndrome spectrum.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Schäfgen
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Cremer
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Becker
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Zink
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kim
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Isabelle C
authors.initials: IC
authors.lastname: Windheuser
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Kreiß
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.|Institute of Human Genetics, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
mesh_terms: D000293:Adolescent; D000067877:Autism Spectrum Disorder / Q000175:diagnosis* / Q000235:genetics; D018389:Codon, Nonsense; D003937:Diagnosis, Differential; D059472:Exome; D016368:Frameshift Mutation; D005877:Gigantism / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D058627:Megalencephaly / Q000175:diagnosis / Q000235:genetics*; D019683:Penetrance; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; C114750:TCF20 protein, human; D014157:Transcription Factors