TY - JOUR
T1 - An excess of deleterious variants in VEGF-A pathway genes in down-syndrome-associated atrioventricular septal defects
AU - Ackerman, Christine
AU - Locke, Adam
AU - Feingold, Eleanor
AU - Reshey, Benjamin
AU - Espana, Karina
AU - Thusberg, Janita
AU - Mooney, Sean
AU - Bean, Lora J.H.
AU - Dooley, Kenneth J.
AU - Cua, Clifford L.
AU - Reeves, Roger H.
AU - Sherman, Stephanie L.
AU - Maslen, Cheryl L.
N1 - Funding Information:
This work was supported in part by NHLBI, R01HD083300 (R.H.R., S.L.S., and C.L.M.), T32 HL094294 (C.A.), the American Heart Association Predoctoral Fellowship Program (A.E.L.), the National Institute for Child Health and Development, F32 HD046337 (L.J.H.B.), the Western Undergraduate Exchange Program, the Portland State University Laurels Scholarship, the Rose Tucker Charitable Trust, the Throckmorton Scholarship Fund (K.E.), Children’s Healthcare of Atlanta Cardiac Research Committee, the National Center for Research Resources (NCRR), UL1RR024140 (OCTRI), and the technical assistance of the General Clinical Research Center at Emory University (National Institutes of Health/NCRR M01 RR00039). Resequencing services were provided by the University of Washington Department of Genome Sciences under U.S. Federal Government contract number N01-HV-48194 from the NHLBI. The authors thank Robert Glanville for critical reading of the manuscript.
PY - 2012/10/5
Y1 - 2012/10/5
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84867274607
U2 - 10.1016/j.ajhg.2012.08.017
DO - 10.1016/j.ajhg.2012.08.017
M3 - Article
C2 - 23040494
AN - SCOPUS:84867274607
SN - 0002-9297
VL - 91
SP - 646
EP - 659
JO - American journal of human genetics
JF - American journal of human genetics
IS - 4
ER -