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Single-molecule optical mapping enables accurate molecular diagnosis of facioscapulohumeral muscular dystrophy (FSHD)

Yi Dai, Pidong Li, Zhiqiang Wang, Fan Liang, Fan Yang, Li Fang, Yu Huang, Shangzhi Huang, Jiapeng Zhou, Depeng Wang, Liying Cui, Kai Wang
doi: https://doi.org/10.1101/286104
Yi Dai
1Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
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Pidong Li
2GrandOmics Biosciences, Beijing, China
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Zhiqiang Wang
3Department of Neurology and Institute of Neurology, First Affiliated Hospital, Center of Neuroscience, Fujian Medical University, Fuzhou, China
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Fan Liang
2GrandOmics Biosciences, Beijing, China
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Fan Yang
2GrandOmics Biosciences, Beijing, China
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Li Fang
4Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
5Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
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Yu Huang
6Department of Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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Shangzhi Huang
7Department of Medical Genetics, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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Jiapeng Zhou
2GrandOmics Biosciences, Beijing, China
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Depeng Wang
2GrandOmics Biosciences, Beijing, China
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Liying Cui
1Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
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  • For correspondence: pumchcuily@sina.com wangk@email.chop.edu
Kai Wang
4Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
5Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
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  • For correspondence: pumchcuily@sina.com wangk@email.chop.edu
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ABSTRACT

Facioscapulohumeral Muscular Dystrophy (FSHD) is a common adult muscular dystrophy in which the muscles of the face, shoulder blades and upper arms are among the most affected. FSHD is the only disease in which “junk” DNA is reactivated to cause disease, and the only known repeat array-related disease where fewer repeats cause disease. More than 95% of FSHD cases are associated with copy number loss of a 3.3kb tandem repeat (D4Z4 repeat) at the subtelomeric chromosomal region 4q35, of which the pathogenic allele contains less than 10 repeats and has a specific genomic configuration called 4qA. Currently, genetic diagnosis of FSHD requires pulsed-field gel electrophoresis followed by Southern blot, which is labor-intensive, semi-quantitative and requires long turnaround time. Here, we developed a novel approach for genetic diagnosis of FSHD, by leveraging Bionano Saphyr single-molecule optical mapping platform. Using a bioinformatics pipeline developed for this assay, we found that the method gives direct quantitative measurement of repeat numbers, can differentiate 4q35 and the highly paralogous 10q26 regions, can determine the 4qA/4qB allelic configuration, and can quantitate levels of post-zygotic mosaicism. We evaluated this approach on 5 patients (including two with post-zygotic mosaicism) and 2 patients (including one with post-zygotic mosaicism) from two separate cohorts, and had complete concordance with Southern blots, but with improved quantification of repeat numbers resolved between haplotypes. We concluded that single-molecule optical mapping is a viable approach for molecular diagnosis of FSHD and may be applied in clinical diagnostic settings once more validations are performed.

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Posted March 21, 2018.
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Single-molecule optical mapping enables accurate molecular diagnosis of facioscapulohumeral muscular dystrophy (FSHD)
Yi Dai, Pidong Li, Zhiqiang Wang, Fan Liang, Fan Yang, Li Fang, Yu Huang, Shangzhi Huang, Jiapeng Zhou, Depeng Wang, Liying Cui, Kai Wang
bioRxiv 286104; doi: https://doi.org/10.1101/286104
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Single-molecule optical mapping enables accurate molecular diagnosis of facioscapulohumeral muscular dystrophy (FSHD)
Yi Dai, Pidong Li, Zhiqiang Wang, Fan Liang, Fan Yang, Li Fang, Yu Huang, Shangzhi Huang, Jiapeng Zhou, Depeng Wang, Liying Cui, Kai Wang
bioRxiv 286104; doi: https://doi.org/10.1101/286104

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