title: Novel loci for non-syndromic coarctation of the aorta in sporadic and familial cases.
abstract: BACKGROUND
  Coarctation of the aorta (CoA) accounts for 5-8% of all congenital heart defects. CoA can be detected in up to 20% of patients with Ullrich-Turner syndrome (UTS), in which a part or all of one of the X chromosomes is absent. The etiology of non-syndromic CoA is poorly understood. In the present work, we test the hypothesis that rare copy number variation (CNV) especially on the gonosomes, contribute to the etiology of non-syndromic CoA.
  
  
  METHODS
  We performed high-resolution genome-wide CNV analysis using the Affymetrix SNP 6.0 microarray platform for 70 individuals with sporadic CoA, 3 families with inherited CoA (n=13) and 605 controls. Our analysis comprised genome wide association, CNV burden and linkage. CNV was validated by multiplex ligation-dependent probe amplification.
  
  
  RESULTS
  We identified a significant abundance of large (>100 kb) CNVs on the X chromosome in males with CoA (p=0.005). 11 out of 51 (~ 22%) male cases had these large CNVs. Association analysis in the sporadic cohort revealed 14 novel loci for CoA. The locus on 21q22.3 in the sporadic CoA cohort overlapped with a gene locus identified in all familial cases of CoA (candidate gene TRPM2). We identified one CNV locus within a locus with high multipoint LOD score from a linkage analysis of the familial cases (SEPT9); another locus overlapped with a region implicated in Kabuki syndrome. In the familial cases, we identified a total of 7 CNV loci that were exclusively present in cases but not in unaffected family members.
  
  
  CONCLUSIONS
  Of all candidate loci identified, the TRPM2 locus was the most frequently implicated autosomal locus in sporadic and familial cases. However, the abundance of large CNVs on the X chromosome of affected males suggests that gonosomal aberrations are not only responsible for syndromic CoA but also involved in the development of sporadic and non-syndromic CoA and their male dominance.
authors.affiliation: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Department of Pediatric Cardiology, Loschgestraße 15, 91054 Erlangen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Moosmann
authors.affiliation: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Institute of Human Genetics, Schwabachanlage 10, 91054 Erlangen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.affiliation: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Department of Pediatric Cardiology, Loschgestraße 15, 91054 Erlangen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Dittrich
authors.affiliation: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Department of Pediatric Cardiac Surgery, Loschgestraße 15, 91054 Erlangen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Rüffer
authors.affiliation: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Institute of Human Genetics, Schwabachanlage 10, 91054 Erlangen, Germany.
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.affiliation: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Department of Pediatric Cardiology, Loschgestraße 15, 91054 Erlangen, Germany.
authors.forename: Okan
authors.initials: O
authors.lastname: Toka
mesh_terms: D000293:Adolescent; D000328:Adult; D001017:Aortic Coarctation / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics; D056915:DNA Copy Number Variations; D005260:Female; D056426:Genetic Loci; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D058112:Septins / Q000235:genetics; D050053:TRPM Cation Channels / Q000235:genetics
chemical_list: D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; C474315:SEPTIN9 protein, human; D058112:Septins