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Molecular combing reveals allelic combinations in facioscapulohumeral dystrophy

Authors

  • Karine Nguyen MD,

    1. AP-HM, Assistance Publique-Hôpitaux de Marseille, Department of Medical Genetics, Timone Children's Hospital, Marseille, France
    2. Aix Marseille University, INSERM UMR_S 910 “Medical Genetics and Functional Genomics,” Marseille, France
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  • Pierre Walrafen PhD,

    1. Genomic Vision, Paris, France
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  • Rafaëlle Bernard MD,

    1. AP-HM, Assistance Publique-Hôpitaux de Marseille, Department of Medical Genetics, Timone Children's Hospital, Marseille, France
    2. Aix Marseille University, INSERM UMR_S 910 “Medical Genetics and Functional Genomics,” Marseille, France
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  • Shahram Attarian MD, PhD,

    1. Aix Marseille University, INSERM UMR_S 910 “Medical Genetics and Functional Genomics,” Marseille, France
    2. AP-HM, Assistance Publique-Hôpitaux de Marseille, Department of Neurology, Reference Center for Neuromuscular Disorders, Timone Hospital, Marseille, France
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  • Charlène Chaix BSc,

    1. AP-HM, Assistance Publique-Hôpitaux de Marseille, Department of Medical Genetics, Timone Children's Hospital, Marseille, France
    2. Genomic Vision, Paris, France
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  • Catherine Vovan BSc,

    1. AP-HM, Assistance Publique-Hôpitaux de Marseille, Department of Medical Genetics, Timone Children's Hospital, Marseille, France
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  • Emilie Renard BSc,

    1. Genomic Vision, Paris, France
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  • Nathalie Dufrane BSc,

    1. Genomic Vision, Paris, France
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  • Jean Pouget MD,

    1. Aix Marseille University, INSERM UMR_S 910 “Medical Genetics and Functional Genomics,” Marseille, France
    2. AP-HM, Assistance Publique-Hôpitaux de Marseille, Department of Neurology, Reference Center for Neuromuscular Disorders, Timone Hospital, Marseille, France
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  • Anne Vannier BSc,

    1. Genomic Vision, Paris, France
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  • Aaron Bensimon PhD,

    1. Genomic Vision, Paris, France
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  • Nicolas Lévy MD, PhD

    Corresponding author
    1. AP-HM, Assistance Publique-Hôpitaux de Marseille, Department of Medical Genetics, Timone Children's Hospital, Marseille, France
    2. Aix Marseille University, INSERM UMR_S 910 “Medical Genetics and Functional Genomics,” Marseille, France
    • Inserm UMR_S 910, Faculté de médecine de Marseille, 13385 Marseille Cedex 05, France
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  • This study is dedicated to Daniel Nerson.

Abstract

Objective:

The genetic variation underlying facioscapulohumeral muscular dystrophy (FSHD), 1 of the most common hereditary neuromuscular disorders, is complex, and associated with the contraction of a repeat array (D4Z4) at the subtelomeric end of chromosome 4q. Nonpathogenic variants of 4q and the presence of a homologous array on chromosome 10q make FSHD diagnosis extremely challenging, at least in individuals with nonstandard D4Z4 arrays. We aimed to improve FSHD molecular analysis by proposing an alternative technique to the Southern blot.

Methods:

We applied molecular combing (MC) to directly visualize allelic combinations associated with FSHD.

Results:

MC enabled the accurate diagnosis of 32 FSHD patients. Unreported haplotypes and rearrangements, as well as somatic mosaicism, which is common in the 10 to 30% of cases that are sporadic, were detectable by MC.

Interpretation:

MC enables the detailed exploration of the FSHD locus and accurate diagnosis of FSHD, the first Mendelian disease to benefit from this technique. MC is also likely to be applicable to other copy number-variant or repeat expansion-associated human diseases. ANN NEUROL 2011;70:627–633

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