Congenital Heart Defects in Patients with Deletions Upstream of SOX9

Authors

  • Marta Sanchez-Castro,

    1. INSERM, UMR1087, l'institut du thorax, Nantes, France
    2. Université de Nantes, Nantes, France
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  • Christopher T. Gordon,

    1. INSERM U781, Hôpital Necker-Enfants Malades, Paris, France
    2. Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, Paris, France
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  • Florence Petit,

    1. Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU Lille, France
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  • Alex S. Nord,

    1. Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California
    2. U.S. Department of Energy, Joint Genome Institute, Walnut Creek, California
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  • Patrick Callier,

    1. Département de Génétique, Hôpital Le Bocage, Dijon, France
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  • Joris Andrieux,

    1. Institut de Génétique Médicale, Hopital Jeanne de Flandre, CHRU de Lille, France
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  • Patrice Guérin,

    1. INSERM, UMR1087, l'institut du thorax, Nantes, France
    2. Université de Nantes, Nantes, France
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  • Olivier Pichon,

    1. CHU Nantes, Service de Génétique Médicale, Nantes, France
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  • Albert David,

    1. CHU Nantes, Service de Génétique Médicale, Nantes, France
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  • Véronique Abadie,

    1. Service de Pédiatrie Générale, Université Paris Descartes, Hôpital Necker-Enfants Malades, Paris, France
    2. CRMR National Reference Centre for Pierre Robin Syndromes and Sucking and Swallowing Congenital Disorders, Paris, France
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  • Damien Bonnet,

    1. Centre de Référence Malformations Cardiaques Congénitales Complexes – M3C, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
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  • Axel Visel,

    1. Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California
    2. U.S. Department of Energy, Joint Genome Institute, Walnut Creek, California
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  • Len A. Pennacchio,

    1. Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California
    2. U.S. Department of Energy, Joint Genome Institute, Walnut Creek, California
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  • Jeanne Amiel,

    1. INSERM U781, Hôpital Necker-Enfants Malades, Paris, France
    2. Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, Paris, France
    3. CRMR National Reference Centre for Pierre Robin Syndromes and Sucking and Swallowing Congenital Disorders, Paris, France
    4. AP-HP, Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France
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  • Stanislas Lyonnet,

    1. INSERM U781, Hôpital Necker-Enfants Malades, Paris, France
    2. Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, Paris, France
    3. CRMR National Reference Centre for Pierre Robin Syndromes and Sucking and Swallowing Congenital Disorders, Paris, France
    4. AP-HP, Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France
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  • Cédric Le Caignec

    Corresponding author
    1. INSERM, UMR1087, l'institut du thorax, Nantes, France
    2. Université de Nantes, Nantes, France
    3. CHU Nantes, Service de Génétique Médicale, Nantes, France
    • Correspondence to: Cédric Le Caignec, Service de Génétique Médicale, CHU, 9, quai Moncousu 44093 Nantes, France. E-mail: cedric.lecaignec@chu-nantes.fr

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  • Contract grant sponsors: PHRC Inter regional (2008); Société Française de Cardiologie/Fédération Française de Cardiologie (2009); Translational Research of Région des Pays de la Loire (2009); École nationale supérieure des mines de Nantes; National Human Genome Research Institute (R01HG003988, U54HG006997); NIDCR (U01-DE020060); NIH/NIGMS F32 Fellowship (GM105202); Agence Nationale de la Recherche (EvoDevoMut 2010).

  • Communicated by Nancy B. Spinner

ABSTRACT

Heterozygous loss-of-function coding-sequence mutations of the transcription factor SOX9 cause campomelic dysplasia, a rare skeletal dysplasia with congenital bowing of long bones (campomelia), hypoplastic scapulae, a missing pair of ribs, pelvic, and vertebral malformations, clubbed feet, Pierre Robin sequence (PRS), facial dysmorphia, and disorders of sex development. We report here two unrelated families that include patients with isolated PRS, isolated congenital heart defect (CHD), or both anomalies. Patients from both families carried a very similar ∼1 Mb deletion upstream of SOX9. Analysis of ChIP-Seq from mouse cardiac tissue for H3K27ac, a marker of active regulatory elements, led us to identify several putative cardiac enhancers within the deleted region. One of these elements is known to interact with Nkx2.5 and Gata4, two transcription factors responsible for CHDs. Altogether, these data suggest that disruption of cardiac enhancers located upstream of SOX9 may be responsible for CHDs in humans.

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