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A Classification Model Relative to Splicing for Variants of Unknown Clinical Significance: Application to the CFTR Gene

Authors

  • Caroline Raynal,

    Corresponding author
    1. Université Montpellier 1, UFR Médecine, Laboratoire de Génétique Moléculaire, Montpellier, France
    • CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, France
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  • David Baux,

    1. CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, France
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  • Corinne Theze,

    1. Université Montpellier 1, UFR Médecine, Laboratoire de Génétique Moléculaire, Montpellier, France
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  • Corinne Bareil,

    1. CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, France
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  • Magali Taulan,

    1. Université Montpellier 1, UFR Médecine, Laboratoire de Génétique Moléculaire, Montpellier, France
    2. Inserm, U827, Montpellier, France
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  • Anne-Françoise Roux,

    1. CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, France
    2. Inserm, U827, Montpellier, France
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  • Mireille Claustres,

    1. CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, France
    2. Université Montpellier 1, UFR Médecine, Laboratoire de Génétique Moléculaire, Montpellier, France
    3. Inserm, U827, Montpellier, France
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  • Sylvie Tuffery-Giraud,

    1. Université Montpellier 1, UFR Médecine, Laboratoire de Génétique Moléculaire, Montpellier, France
    2. Inserm, U827, Montpellier, France
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  • Marie des Georges

    1. CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, France
    2. Inserm, U827, Montpellier, France
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  • Communicated by Rachel Karchin

  • Additional Supporting Information may be found in the online version of this article.

Correspondence to: Caroline Raynal, Laboratoire de Génétique Moléculaire, INSERM U827, Institut Universitaire de Recherche Clinique, 34093 Montpellier Cedex 5, France. E-mail: caroline.raynal@inserm.fr

ABSTRACT

Molecular diagnosis of cystic fibrosis and cystic fibrosis transmembrane regulator (CFTR)-related disorders led to the worldwide identification of nearly 1,900 sequence variations in the CFTR gene that consist mainly of private point mutations and small insertions/deletions. Establishing their effect on the function of the encoded protein and therefore their involvement in the disease is still challenging and directly impacts genetic counseling. In this context, we built a decision tree following the international guidelines for the classification of variants of unknown clinical significance (VUCS) in the CFTR gene specifically focused on their consequences on splicing. We applied general and specific criteria, including comprehensive review of literature and databases, familial genetics data, and thorough in silico studies. This model was tested on 15 intronic and exonic VUCS identified in our cohort. Six variants were classified as probably nonpathogenic considering their impact on splicing and eight as probably pathogenic, which include two apparent missense mutations. We assessed the validity of our method by performing minigenes studies and confirmed that 93% (14/15) were correctly classified. We provide in this study a high-performance method that can play a full role in interpreting the results of molecular diagnosis in emergency context, when functional studies are not achievable.

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