title: An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects.
abstract: About half of people with trisomy 21 have a congenital heart defect (CHD), whereas the remainder have a structurally normal heart, demonstrating that trisomy 21 is a significant risk factor but is not causal for abnormal heart development. Atrioventricular septal defects (AVSD) are the most commonly occurring heart defects in Down syndrome (DS), and ∼65% of all AVSD is associated with DS. We used a candidate-gene approach among individuals with DS and complete AVSD (cases = 141) and DS with no CHD (controls = 141) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. We found a significant excess (p < 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, we found potentially damaging variants in nearly 20% of cases but fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in six genes: COL6A1, COL6A2, CRELD1, FBLN2, FRZB, and GATA5. Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGF-A pathway, even though the candidate genes analyzed in this study represented numerous biochemical and developmental pathways, suggesting that rare variants in the VEGF-A pathway might contribute to the genetic underpinnings of AVSD in humans.
authors.affiliation: Division of Cardiovascular Medicine and the Heart Research Center, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Ackerman
authors.forename: Adam E
authors.initials: AE
authors.lastname: Locke
authors.forename: Eleanor
authors.initials: E
authors.lastname: Feingold
authors.forename: Benjamin
authors.initials: B
authors.lastname: Reshey
authors.forename: Karina
authors.initials: K
authors.lastname: Espana
authors.forename: Janita
authors.initials: J
authors.lastname: Thusberg
authors.forename: Sean
authors.initials: S
authors.lastname: Mooney
authors.forename: Lora J H
authors.initials: LJ
authors.lastname: Bean
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Dooley
authors.forename: Clifford L
authors.initials: CL
authors.lastname: Cua
authors.forename: Roger H
authors.initials: RH
authors.lastname: Reeves
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Sherman
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Maslen
mesh_terms: D016022:Case-Control Studies; D004314:Down Syndrome / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006344:Heart Septal Defects, Atrial / Q000235:genetics*; D006345:Heart Septal Defects, Ventricular / Q000235:genetics*; D006801:Humans; D022661:RNA, Untranslated / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D022661:RNA, Untranslated; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A