title: Genome-wide mapping of copy number variations in patients with both anorectal malformations and central nervous system abnormalities.
abstract: BACKGROUND
  Anorectal malformations (ARM) have a prevalence of around 1 in 2500 live births. In around 50% of patients, the malformation is isolated, while in the remainder it arises within the context of complex genetic abnormalities or a defined genetic syndrome. Recent studies have implicated rare copy number variations (CNVs) in both isolated and nonisolated ARM, and identified plausible candidate genes.
  
  
  METHODS
  In the present study, array-based molecular karyotyping was performed to identify causative CNVs in 32 sporadic ARM patients with comorbid abnormalities of the central nervous system (CNS). This phenotype was selected to enrich for rare CNVs, since previous research has implicated rare CNVs in both CNS abnormalities and ARM.
  
  
  RESULTS
  In five patients, a probable disease-causing CNV was identified (del6q14.3q16.3, del14q32.2, del17q12q21.2, and two patients with del22q11.21). In three of these patients, the CNVs were de novo. For the remaining two patients, no parental DNA was available. Deletions at 22q11.21 and 6q14.3 have been associated with both CNS abnormalities and ARM. In contrast, deletions at 14q32.2 have only been described in patients with CNS abnormalities, and the del17q12q21.2 is a novel CNV. Expression studies in mice suggest that NEUROD2 and RARA, which reside within the newly identified del17q12q21.2 region, are candidate genes for the formation of microcephaly and ARM.
  
  
  CONCLUSIONS
  The present data suggest that CNVs are a frequent cause of the ARM with CNS abnormalities phenotype, and that array-analysis is indicated in such patients.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Gabriel C
authors.initials: GC
authors.lastname: Dworschak
authors.forename: Markus
authors.initials: M
authors.lastname: Draaken
authors.forename: Alina C
authors.initials: AC
authors.lastname: Hilger
authors.forename: Charlotte
authors.initials: C
authors.lastname: Schramm
authors.forename: Enrika
authors.initials: E
authors.lastname: Bartels
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schmiedeke
authors.forename: Sabine
authors.initials: S
authors.lastname: Grasshoff-Derr
authors.forename: Stefanie
authors.initials: S
authors.lastname: Märzheuser
authors.forename: Stefan
authors.initials: S
authors.lastname: Holland-Cunz
authors.forename: Martin
authors.initials: M
authors.lastname: Lacher
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Jenetzky
authors.forename: Nadine
authors.initials: N
authors.lastname: Zwink
authors.forename: Dominik
authors.initials: D
authors.lastname: Schmidt
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
authors.forename: Heiko
authors.initials: H
authors.lastname: Reutter
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D001003:Anal Canal / Q000002:abnormalities* / Q000473:pathology; D000071056:Anorectal Malformations; D001006:Anus, Imperforate / Q000235:genetics* / Q000473:pathology; D002490:Central Nervous System / Q000002:abnormalities*; D002648:Child; D002872:Chromosome Deletion; D002874:Chromosome Mapping / Q000379:methods; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007621:Karyotyping; D008297:Male; D012007:Rectum / Q000002:abnormalities* / Q000473:pathology; D055815:Young Adult
keywords: ARM; CNV analysis; SNP array; central nervous system; contiguous gene syndrome; de novo; deletions