title: Array-based molecular karyotyping in fetuses with isolated brain malformations identifies disease-causing CNVs.
abstract: BACKGROUND
  The overall birth prevalence for congenital malformations of the central nervous system (CNS) among Europeans may be as high as 1 in 100 live births. The etiological factors remain largely unknown. The aim of this study was to detect causative copy number variations (CNVs) in fetuses of terminated pregnancies with prenatally detected isolated brain malformations.
  
  
  METHODS
  Array-based molecular karyotyping was performed in a cohort of 35 terminated fetuses with isolated CNS malformations. Identified putative disease-causing CNVs were confirmed using quantitative polymerase chain reaction or multiplex ligation-dependent probe amplification.
  
  
  RESULTS
  Based on their de novo occurrence and/or their established association with congenital brain malformations, we detected five disease-causing CNVs in four fetuses involving chromosomal regions 6p25.1-6p25.3 (FOXC1), 6q27, 16p12.3, Xp22.2-Xp22.32 (MID1), and Xp22.32-Xp22.33. Furthermore, we detected a probably disease-causing CNV involving chromosomal region 3p26.3 in one fetus, and in addition, we detected 12 CNVs in nine fetuses of unknown clinical significance. All CNVs except for two were absent in 1307 healthy in-house controls (frequency <0.0008). Each of the two CNVs present in in-house controls was present only once (frequency = 0.0008). Furthermore, our data suggests the involvement of CNTN6 and KLHL15 in the etiology of agenesis of the corpus callosum, the involvement of RASD1 and PTPRD in Dandy-Walker malformation, and the involvement of ERMARD in ventriculomegaly.
  
  
  CONCLUSIONS
  Our study suggests that CNVs play an important role in the etiology of isolated brain malformations.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Madita
authors.initials: M
authors.lastname: Schumann
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany ; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hofmann
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Sophia K
authors.initials: SK
authors.lastname: Krutzke
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Alina C
authors.initials: AC
authors.lastname: Hilger
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Marsch
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Dietlinde
authors.initials: D
authors.lastname: Stienen
authors.affiliation: Department of Obstetrics and Prenatal Medicine, University of Bonn Medical School, Bonn, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Gembruch
authors.affiliation: Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
authors.affiliation: Department of Obstetrics and Prenatal Medicine, University of Bonn Medical School, Bonn, Germany.
authors.forename: Waltraut M
authors.initials: WM
authors.lastname: Merz
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany ; Department of Neonatology and Pediatric Intensive Care & Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, D-53127 Bonn, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Reutter
keywords: Array-based karyotyping; Brain malformation; Copy number variation (CNV); De novo occurrence