Genetic modifiers predisposing to congenital heart disease in the sensitized down syndrome population

Huiqing Li, Sheila Cherry, Donna Klinedinst, Valerie DeLeon, Jennifer Redig, Benjamin Reshey, Michael T. Chin, Stephanie L. Sherman, Cheryl Maslen, Roger H. Reeves

    Research output: Contribution to journalArticle

    35 Citations (Scopus)

    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. Methods and 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.

    Original languageEnglish (US)
    Pages (from-to)301-308
    Number of pages8
    JournalCirculation: Cardiovascular Genetics
    Volume5
    Issue number3
    DOIs
    StatePublished - Jun 2012

    Fingerprint

    Down Syndrome
    Heart Diseases
    Population
    Modifier Genes
    Chromosomes, Human, Pair 21
    Gene Dosage
    Trisomy
    Population Genetics
    Human Chromosomes
    Genes
    Alleles

    Keywords

    • Congenital heart disease
    • Down syndrome
    • Genetic modifier

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine
    • Genetics(clinical)
    • Genetics

    Cite this

    Genetic modifiers predisposing to congenital heart disease in the sensitized down syndrome population. / Li, Huiqing; Cherry, Sheila; Klinedinst, Donna; DeLeon, Valerie; Redig, Jennifer; Reshey, Benjamin; Chin, Michael T.; Sherman, Stephanie L.; Maslen, Cheryl; Reeves, Roger H.

    In: Circulation: Cardiovascular Genetics, Vol. 5, No. 3, 06.2012, p. 301-308.

    Research output: Contribution to journalArticle

    Li, H, Cherry, S, Klinedinst, D, DeLeon, V, Redig, J, Reshey, B, Chin, MT, Sherman, SL, Maslen, C & Reeves, RH 2012, 'Genetic modifiers predisposing to congenital heart disease in the sensitized down syndrome population', Circulation: Cardiovascular Genetics, vol. 5, no. 3, pp. 301-308. https://doi.org/10.1161/CIRCGENETICS.111.960872
    Li, Huiqing ; Cherry, Sheila ; Klinedinst, Donna ; DeLeon, Valerie ; Redig, Jennifer ; Reshey, Benjamin ; Chin, Michael T. ; Sherman, Stephanie L. ; Maslen, Cheryl ; Reeves, Roger H. / Genetic modifiers predisposing to congenital heart disease in the sensitized down syndrome population. In: Circulation: Cardiovascular Genetics. 2012 ; Vol. 5, No. 3. pp. 301-308.
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    AU - Redig, Jennifer

    AU - Reshey, Benjamin

    AU - Chin, Michael T.

    AU - Sherman, Stephanie L.

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    AU - Reeves, Roger H.

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    AB - 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. Methods and 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.

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