title: Genetic modifiers predisposing to congenital heart disease in the sensitized Down syndrome population.
abstract: BACKGROUND
  About half of people with Down syndrome (DS) exhibit some form of congenital heart disease (CHD); however, trisomy for human chromosome 21 (Hsa21) alone is insufficient to cause CHD, as half of all people with DS have a normal heart, suggesting that genetic modifiers interact with dosage-sensitive gene(s) on Hsa21 to result in CHD. We hypothesize that a threshold exists in both DS and euploid populations for the number of genetic perturbations that can be tolerated before CHD results.
  
  
  RESULTS
  We ascertained a group of individuals with DS and complete atrioventricular septal defect and sequenced 2 candidate genes for CHD: CRELD1, which is associated with atrioventricular septal defect in people with or without DS, and HEY2, whose mouse ortholog (Hey2) produces septal defects when mutated. Several deleterious variants were identified, but the frequency of these potential modifiers was low. We crossed mice with mutant forms of these potential modifiers to the Ts65Dn mouse model of DS. Crossing loss-of-function alleles of either Creld1 or Hey2 onto the trisomic background caused a significant increase in the frequency of CHD, demonstrating an interaction between the modifiers and trisomic genes. We showed further that, although each of these mutant modifiers is benign by itself, they interact to affect heart development when inherited together.
  
  
  CONCLUSIONS
  Using mouse models of Down syndrome and of genes associated with congenital heart disease, we demonstrate a biological basis for an interaction that supports a threshold hypothesis for additive effects of genetic modifiers in the sensitized trisomic population.
authors.affiliation: Department of Physiology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Li
authors.forename: Sheila
authors.initials: S
authors.lastname: Cherry
authors.forename: Donna
authors.initials: D
authors.lastname: Klinedinst
authors.forename: Valerie
authors.initials: V
authors.lastname: DeLeon
authors.forename: Jennifer
authors.initials: J
authors.lastname: Redig
authors.forename: Benjamin
authors.initials: B
authors.lastname: Reshey
authors.forename: Michael T
authors.initials: MT
authors.lastname: Chin
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Sherman
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Maslen
authors.forename: Roger H
authors.initials: RH
authors.lastname: Reeves
mesh_terms: D000483:Alleles; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006330:Heart Defects, Congenital / Q000150:complications / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014314:Trisomy
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D012097:Repressor Proteins; C465506:CRELD1 protein, human; C405693:HEY2 protein, human; C485778:Hey2 protein, mouse