title: Array-based molecular karyotyping in fetal brain malformations: Identification of novel candidate genes and chromosomal regions.
abstract: BACKGROUND
  For the majority of congenital brain malformations, the underlying cause remains unknown. Recent studies have implicated rare copy number variations (CNVs) in their etiology.
  
  
  METHODS
  Here, we used array-based molecular karyotyping to search for causative CNVs in 33 fetuses of terminated pregnancies with prenatally detected brain malformations and additional extracerebral anomalies.
  
  
  RESULTS
  In 11 fetuses, we identified 15 CNVs (0.08 Mb to 29.59 Mb), comprising four duplications and eleven deletions. All larger CNVs (> 5 Mb) had also been detected by prenatal conventional karyotyping. None of these CNVs was present in our 1307 healthy in-house controls (frequency < 0.0008). Among these CNVs, we prioritized six chromosomal regions (1q25.1, 5q35.1, 6q25.3-qter, 11p14.3, 15q11.2-q13.1, 18q21.1) due to their previous association with human brain malformations or owing to the presence of a single gene expressed in human brain. Prioritized genes within these regions were UBTD2, SKA1, SVIP, and, most convincingly, GPR52. However, re-sequencing of GPR52 in 100 samples from fetuses with brain malformations or patients with intellectual disability and brain malformations revealed no disease-causing mutation.
  
  
  CONCLUSIONS
  Our study suggests chromosomal regions 1q25.1, 5q35.1, 6q25.3-qter, 11p14.3, 15q11.2-q13.1, and 18q21.1 to be involved in human brain development. Within three of these regions, we suggest UBTD2, GPR52, and SKA1 as possible candidate genes. Because the overall detection rate of array-based molecular karyotyping was slightly higher (23%) than that of conventional prenatal karyotyping (20%), we suggest it's use for prenatal diagnostic testing in fetuses with nonisolated brain malformations.
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: Hartmut
authors.initials: H
authors.lastname: Engels
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: Madita M
authors.initials: MM
authors.lastname: Schumann
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: Alexander M
authors.initials: AM
authors.lastname: Zink
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Hilger
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, Bonn, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Gembruch
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Reutter
authors.affiliation: Department of Obstetrics and Prenatal Medicine, University of Bonn, Bonn, Germany.
authors.forename: Waltraut M
authors.initials: WM
authors.lastname: Merz
mesh_terms: D000328:Adult; D001921:Brain / Q000002:abnormalities / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations; D005260:Female; D005333:Fetus; D018628:Gene Dosage; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D007621:Karyotyping / Q000295:instrumentation / Q000379:methods; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009421:Nervous System Malformations / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D028044:Phosphate-Binding Proteins; D011247:Pregnancy; D011296:Prenatal Diagnosis; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D002868:Chromosomal Proteins, Non-Histone; D008565:Membrane Proteins; D018832:Molecular Chaperones; D028044:Phosphate-Binding Proteins; C516427:SKA1 protein, human; C569017:SVIP protein, human; D014452:Ubiquitins
keywords: CNS; CNV analysis; SNP array; central nervous system; copy number variations; de novo; deletions