Novel loci for non-syndromic coarctation of the aorta in sporadic and familial cases

PLoS One. 2015 May 18;10(5):e0126873. doi: 10.1371/journal.pone.0126873. eCollection 2015.


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.

Conclusion: 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.

MeSH terms

  • Adolescent
  • Adult
  • Aortic Coarctation / genetics*
  • Child
  • Child, Preschool
  • Chromosomes, Human, X / genetics
  • DNA Copy Number Variations*
  • Female
  • Genetic Loci*
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Pedigree
  • Septins / genetics
  • TRPM Cation Channels / genetics


  • TRPM Cation Channels
  • TRPM2 protein, human
  • SEPTIN9 protein, human
  • Septins

Associated data

  • GEO/GSE67929
  • GEO/GSE67930

Grants and funding

The authors have no support or funding to report.