An excess of deleterious variants in VEGF-A pathway genes in down-syndrome-associated atrioventricular septal defects

Christine Ackerman, Adam E. Locke, Eleanor Feingold, Benjamin Reshey, Karina Espana, Janita Thusberg, Sean Mooney, Lora J H Bean, Kenneth J. Dooley, Clifford L. Cua, Roger H. Reeves, Stephanie L. Sherman, Cheryl Maslen

    Research output: Contribution to journalArticle

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    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.

    Original languageEnglish (US)
    Pages (from-to)646-659
    Number of pages14
    JournalAmerican Journal of Human Genetics
    Volume91
    Issue number4
    DOIs
    StatePublished - Oct 5 2012

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    Down Syndrome
    Vascular Endothelial Growth Factor A
    Genes
    Congenital Heart Defects
    Morphogenesis
    Atrioventricular Septal Defect
    Population

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)

    Cite this

    An excess of deleterious variants in VEGF-A pathway genes in down-syndrome-associated atrioventricular septal defects. / Ackerman, Christine; Locke, Adam E.; Feingold, Eleanor; Reshey, Benjamin; Espana, Karina; Thusberg, Janita; Mooney, Sean; Bean, Lora J H; Dooley, Kenneth J.; Cua, Clifford L.; Reeves, Roger H.; Sherman, Stephanie L.; Maslen, Cheryl.

    In: American Journal of Human Genetics, Vol. 91, No. 4, 05.10.2012, p. 646-659.

    Research output: Contribution to journalArticle

    Ackerman, C, Locke, AE, Feingold, E, Reshey, B, Espana, K, Thusberg, J, Mooney, S, Bean, LJH, Dooley, KJ, Cua, CL, Reeves, RH, Sherman, SL & Maslen, C 2012, 'An excess of deleterious variants in VEGF-A pathway genes in down-syndrome-associated atrioventricular septal defects', American Journal of Human Genetics, vol. 91, no. 4, pp. 646-659. https://doi.org/10.1016/j.ajhg.2012.08.017
    Ackerman, Christine ; Locke, Adam E. ; Feingold, Eleanor ; Reshey, Benjamin ; Espana, Karina ; Thusberg, Janita ; Mooney, Sean ; Bean, Lora J H ; Dooley, Kenneth J. ; Cua, Clifford L. ; Reeves, Roger H. ; Sherman, Stephanie L. ; Maslen, Cheryl. / An excess of deleterious variants in VEGF-A pathway genes in down-syndrome-associated atrioventricular septal defects. In: American Journal of Human Genetics. 2012 ; Vol. 91, No. 4. pp. 646-659.
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    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.",
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    AU - Ackerman, Christine

    AU - Locke, Adam E.

    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

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    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.

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