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Whole-genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype

Authors

  • G D'Amours,

    1. Service de Génétique Médicale
    2. Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada
    3. Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
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  • Z Kibar,

    1. Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada
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  • G Mathonnet,

    1. Service de Génétique Médicale
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  • R Fetni,

    1. Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada
    2. Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
    3. Département de Pathologie, CHU Sainte-Justine, Montréal, QC, Canada
    4. Département de Pathologie et Biologie Cellulaire
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  • F Tihy,

    1. Service de Génétique Médicale
    2. Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada
    3. Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
    4. Département de Pathologie et Biologie Cellulaire
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  • V Désilets,

    1. Service de Génétique Médicale
    2. Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
    3. Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada
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  • S Nizard,

    1. Service de Génétique Médicale
    2. Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
    3. Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada
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  • JL Michaud,

    1. Service de Génétique Médicale
    2. Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada
    3. Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
    4. Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada
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  • E Lemyre

    Corresponding author
    1. Service de Génétique Médicale
    2. Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada
    3. Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
    4. Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada
      Emmanuelle Lemyre, MD, FRCPC, FCCMG, Service de Génétique Médicale, CHU Sainte-Justine, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada.
      Tel.: +1 514 345-4931x6342;
      fax: +1 514 345-4766;
      e-mail: emmanuelle.lemyre@recherche-ste-justine.qc.ca
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Emmanuelle Lemyre, MD, FRCPC, FCCMG, Service de Génétique Médicale, CHU Sainte-Justine, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada.
Tel.: +1 514 345-4931x6342;
fax: +1 514 345-4766;
e-mail: emmanuelle.lemyre@recherche-ste-justine.qc.ca

Abstract

D’Amours G, Kibar Z, Mathonnet G, Fetni R, Tihy F, Désilets V, Nizard S, Michaud JL, Lemyre E. Whole-genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype.

Despite a wide range of clinical tools, the etiology of mental retardation and multiple congenital malformations remains unknown for many patients. Array-based comparative genomic hybridization (aCGH) has proven to be a valuable tool in these cases, as its pangenomic coverage allows the identification of chromosomal aberrations that are undetectable by other genetic methods targeting specific genomic regions. Therefore, aCGH is increasingly used in clinical genetics, both in the postnatal and the prenatal settings. While the diagnostic yield in the postnatal population has been established at 10–12%, studies investigating fetuses have reported variable results. We used whole-genome aCGH to investigate fetuses presenting at least one major malformation detected on ultrasound, but for whom standard genetic analyses (including karyotype) failed to provide a diagnosis. We identified a clinically significant chromosomal aberration in 8.2% of tested fetuses (4/49), and a result of unclear clinical significance in 12.2% of tested fetuses (6/49). Our results document the value of whole-genome aCGH as a prenatal diagnostic tool and highlight the interpretation difficulties associated with copy number variations of unclear significance.

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