title: Truncating de novo mutations in the Krüppel-type zinc-finger gene ZNF148 in patients with corpus callosum defects, developmental delay, short stature, and dysmorphisms.
abstract: Krüppel-type zinc finger genes (ZNF) constitute a large yet relatively poorly characterized gene family. ZNF genes encode proteins that recognize specific DNA motifs in gene promotors. They act as transcriptional co-activators or -repressors via interaction with chromatin remodeling proteins and other transcription factors. Only few ZNF genes are currently linked to human disorders and identification of ZNF gene-associated human diseases may help understand their function. Here we provide genetic, statistical, and clinical evidence to support association of ZNF148 with a new intellectual disability (ID) syndrome disorder.
  
  
  
  Routine diagnostic exome sequencing data were obtained from 2172 patients with ID and/or multiple congenital anomalies.
  
  
  
  In a cohort of 2172 patient-parent trios referred for routine diagnostic whole exome sequencing for ID and/or multiple congenital anomalies (MCA) in the period 2012-2016, four patients were identified who carried de novo heterozygous nonsense or frameshift mutations in the ZNF148 gene. This was the only ZNF gene with recurrent truncating de novo mutations in this cohort. All mutations resulted in premature termination codons in the last exon of ZNF148. The number of the de novo truncating mutations in the ZNF148 gene was significantly enriched (p = 5.42 × 10-3). The newly described ZNF148-associated syndrome is characterized by underdevelopment of the corpus callosum, mild to moderate developmental delay and ID, variable microcephaly or mild macrocephaly, short stature, feeding problems, facial dysmorphisms, and cardiac and renal malformations.
  
  
  
  We propose ZNF148 as a gene involved in a newly described ID syndrome with a recurrent phenotype and postulate that the ZNF148 is a hitherto unrecognized but crucial transcription factor in the development of the corpus callosum. Our study illustrates the advantage of whole exome sequencing in a large cohort using a parent-offspring trio approach for identifying novel genes involved in rare human diseases.
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center (MUMC+), PO Box 5800, 6202, AZ, Maastricht, The Netherlands. servi.stevens@mumc.nl.
authors.forename: Servi J C
authors.initials: SJ
authors.lastname: Stevens
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
authors.forename: Anthonie J
authors.initials: AJ
authors.lastname: van Essen
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
authors.forename: Conny M A
authors.initials: CM
authors.lastname: van Ravenswaaij
authors.affiliation: Department of Medical Genetics, Shodair Children's Hospital, Helena, MT, USA.
authors.forename: Abdallah F
authors.initials: AF
authors.lastname: Elias
authors.affiliation: Department of Medical Genetics, Shodair Children's Hospital, Helena, MT, USA.
authors.forename: Jaclyn A
authors.initials: JA
authors.lastname: Haven
authors.affiliation: Department of Genetics, Radboud University Medical Center (RUMC), Nijmegen, The Netherlands.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Lelieveld
authors.affiliation: Department of Genetics, Radboud University Medical Center (RUMC), Nijmegen, The Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Genetics, Radboud University Medical Center (RUMC), Nijmegen, The Netherlands.
authors.forename: Willy M
authors.initials: WM
authors.lastname: Nillesen
authors.affiliation: Department of Genetics, Radboud University Medical Center (RUMC), Nijmegen, The Netherlands.
authors.forename: Helger G
authors.initials: HG
authors.lastname: Yntema
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center (MUMC+), PO Box 5800, 6202, AZ, Maastricht, The Netherlands.|Department of Genetics, Radboud University Medical Center (RUMC), Nijmegen, The Netherlands.
authors.forename: Kees
authors.initials: K
authors.lastname: van Roozendaal
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center (MUMC+), PO Box 5800, 6202, AZ, Maastricht, The Netherlands.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Stegmann
authors.affiliation: Department of Genetics, Radboud University Medical Center (RUMC), Nijmegen, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center (MUMC+), PO Box 5800, 6202, AZ, Maastricht, The Netherlands.|Department of Genetics, Radboud University Medical Center (RUMC), Nijmegen, The Netherlands.
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D057215:Body Dysmorphic Disorders / Q000235:genetics* / Q000473:pathology; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; C110951:ZNF148 protein, human
keywords: Corpus callosum development; De novo mutations; Intellectual disability; Premature termination codon; Whole exome sequencing; ZBP-89; ZNF148