title: Loss-of-function variants in HIVEP2 are a cause of intellectual disability.
abstract: Intellectual disability (ID) affects 2-3% of the population. In the past, many genetic causes of ID remained unidentified due to its vast heterogeneity. Recently, whole exome sequencing (WES) studies have shown that de novo variants underlie a significant portion of sporadic cases of ID. Applying WES to patients with ID or global developmental delay at different centers, we identified three individuals with distinct de novo variants in HIVEP2 (human immunodeficiency virus type I enhancer binding protein), which belongs to a family of zinc-finger-containing transcriptional proteins involved in growth and development. Two of the variants were nonsense changes, and one was a 1 bp deletion resulting in a premature stop codon that was reported previously without clinical detail. In silico prediction programs suggest loss-of-function in the mutated allele leading to haploinsufficiency as a putative mechanism in all three individuals. All three patients presented with moderate-to-severe ID, minimal structural brain anomalies, hypotonia, and mild dysmorphic features. Growth parameters were in the normal range except for borderline microcephaly at birth in one patient. Two of the patients exhibited behavioral anomalies including hyperactivity and aggression. Published functional data suggest a neurodevelopmental role for HIVEP2, and several of the genes regulated by HIVEP2 are implicated in brain development, for example, SSTR-2, c-Myc, and genes of the NF-κB pathway. In addition, HIVEP2-knockout mice exhibit several working memory deficits, increased anxiety, and hyperactivity. On the basis of the genotype-phenotype correlation and existing functional data, we propose HIVEP2 as a causative ID gene.
authors.affiliation: Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.|Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.affiliation: Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Schanze
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, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: CeGaT GmbH, Tuebingen, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Menzel
authors.affiliation: CeGaT GmbH, Tuebingen, Germany.
authors.forename: Max
authors.identifier: http://orcid.org/0000-0001-9726-6662
authors.initials: M
authors.lastname: Schubach
authors.affiliation: CeGaT GmbH, Tuebingen, Germany.|Hertie Institute for Clinical Brain Research, German Center for Neurodegenerative Diseases, Tuebingen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
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, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Endele
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.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.affiliation: Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Cohen
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Zink
authors.affiliation: Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.|Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: SakkuBai
authors.initials: S
authors.lastname: Naidu
mesh_terms: D002675:Child, Preschool; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C077171:HIVEP2 protein, human