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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
Chinese Academy of Medical Sciences;
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Pidong Li
GrandOmics Biosciences;
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Zhiqiang Wang
Fujian Medical University;
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Fan Liang
GrandOmics Biosciences;
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Fan Yang
GrandOmics Biosciences;
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Li Fang
Children's Hospital of Philadelphia;
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Yu Huang
Peking University Health Science Center
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Shangzhi Huang
Chinese Academy of Medical Sciences;
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Jiapeng Zhou
GrandOmics Biosciences;
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Depeng Wang
GrandOmics Biosciences;
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Liying Cui
Chinese Academy of Medical Sciences;
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Kai Wang
Children's Hospital of Philadelphia;
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  • For correspondence: kaichop@gmail.com
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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 was reactivated to cause disease, and the only repeat-related disease where less 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 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 measures of repeat numbers, can differentiate 4q35 and the highly paralogous 10q26 region, 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. 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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The copyright holder for this preprint is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
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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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