title: Search for Rare Copy-Number Variants in Congenital Heart Defects Identifies Novel Candidate Genes and a Potential Role for FOXC1 in Patients With Coarctation of the Aorta.
abstract: BACKGROUND
  Congenital heart defects are the most frequent malformations among newborns and a frequent cause of morbidity and mortality. Although genetic variation contributes to congenital heart defects, their precise molecular bases remain unknown in the majority of patients.
  
  
  RESULTS
  We analyzed, by high-resolution array comparative genomic hybridization, 316 children with sporadic, nonsyndromic congenital heart defects, including 76 coarctation of the aorta, 159 transposition of the great arteries, and 81 tetralogy of Fallot, as well as their unaffected parents. We identified by array comparative genomic hybridization, and validated by quantitative real-time polymerase chain reaction, 71 rare de novo (n=8) or inherited (n=63) copy-number variants (CNVs; 50 duplications and 21 deletions) in patients. We identified 113 candidate genes for congenital heart defects within these CNVs, including BTRC, CHRNB3, CSRP2BP, ERBB2, ERMARD, GLIS3, PLN, PTPRJ, RLN3, and TCTE3. No de novo CNVs were identified in patients with transposition of the great arteries in contrast to coarctation of the aorta and tetralogy of Fallot (P=0.002; Fisher exact test). A search for transcription factor binding sites showed that 93% of the rare CNVs identified in patients with coarctation of the aorta contained at least 1 gene with FOXC1-binding sites. This significant enrichment (P<0.0001; permutation test) was not observed for the CNVs identified in patients with transposition of the great arteries and tetralogy of Fallot. We hypothesize that these CNVs may alter the expression of genes regulated by FOXC1. Foxc1 belongs to the forkhead transcription factors family, which plays a critical role in cardiovascular development in mice.
  
  
  CONCLUSIONS
  These data suggest that deregulation of FOXC1 or its downstream genes play a major role in the pathogenesis of coarctation of the aorta in humans.
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez-Castro
authors.forename: Hadja
authors.initials: H
authors.lastname: Eldjouzi
authors.forename: Eric
authors.initials: E
authors.lastname: Charpentier
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Busson
authors.forename: Quentin
authors.initials: Q
authors.lastname: Hauet
authors.forename: Pierre
authors.initials: P
authors.lastname: Lindenbaum
authors.forename: Béatrice
authors.initials: B
authors.lastname: Delasalle-Guyomarch
authors.forename: Adrien
authors.initials: A
authors.lastname: Baudry
authors.forename: Olivier
authors.initials: O
authors.lastname: Pichon
authors.forename: Cécile
authors.initials: C
authors.lastname: Pascal
authors.forename: Bruno
authors.initials: B
authors.lastname: Lefort
authors.forename: Fanny
authors.initials: F
authors.lastname: Bajolle
authors.forename: Philippe
authors.initials: P
authors.lastname: Pezard
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
authors.forename: Christian
authors.initials: C
authors.lastname: Dina
authors.forename: Richard
authors.initials: R
authors.lastname: Redon
authors.forename: Véronique
authors.initials: V
authors.lastname: Gournay
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.forename: Cédric
authors.initials: C
authors.lastname: Le Caignec
mesh_terms: D000818:Animals; D001017:Aortic Coarctation / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D009426:Netherlands
chemical_list: C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse
keywords: coarctation of the aorta; comparative genomic hybridization; congenital heart disease; copy-number variants; forkhead transcription factors; humans; tetralogy of Fallot