biostudies-literature00440Ackerman CNICHD NIH HHSNCATS NIH HHSNCRR NIH HHSNHLBI NIH HHSNHGRI NIH HHSNLM NIH HHSNIGMS NIH HHS646-59https://www.ebi.ac.uk/biostudies/studies/S-EPMC3484504biostudies-literatureUnknown91(4)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.American journal of human geneticsAn excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects.PMC3484504T32 HL094294N01-HV-48194UL1RR024140UL1 TR000454R01HD083300R01 LM009722UL1 TR000128N01HV48194U54 HG004028M01 RR00039UL1 RR025008M01 RR000039T32 GM008490UL1 RR024140F32 HD046337Ackerman CReshey BSherman SLLocke AEFeingold ECua CLThusberg JBean LJMaslen CLReeves RHDooley KJEspana KMooney S44falseAn excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects.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.2012-01-01T00:00:00Z2012 Oct2024-02-16T06:15:49.896Z2019-03-27T00:59:41ZS-EPMC34845042304049410.1016/j.ajhg.2012.08.017