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Abstract
Background Facioscapulohumeral muscular dystrophy 1 (FSHD1) is an autosomal dominant muscular disorder mainly caused by the contraction and hypomethylation of the D4Z4 repeat array in chromosome 4q35. Prenatal diagnosis of FSHD1 is challenging due to the highly repetitive and long genomic structure. In this study, a pregnant woman diagnosed with FSHD1 using optical genome mapping sought assistance for a healthy offspring.
Methods At the 17th week of gestation, she underwent amniocentesis, and genomic DNA (gDNA) was extracted from amniocytes. Whole-genome sequencing of the gDNA was performed using the nanopore MinION platform.
Results Despite a sequencing depth of only 7.3×, bioinformatic analyses revealed that the fetus inherited four D4Z4 repeat units with the permissive 4qA from the mother and the eight D4Z4 repeat units with the non-permissive 4qB from the father. To validate the results, SNP-based linkage analyses were conducted with gDNA from the proband, the proband’s father and proband’s amniocytes. Results indicated that the fetus inherited the maternal pathogenic haplotype based on 144 informative SNPs. Linkage analysis was consistent with the nanopore sequencing.
Conclusion Nanopore sequencing proves to be an accurate and direct method for genetic testing of monogenic diseases at the single-nucleotide level. This study represents the first application of nanopore sequencing in the prenatal diagnosis of FSHD1, providing a significant advantage for patients with de novo mutations.
- Nanopore Sequencing
Data availability statement
Data are available in a public, open access repository. The original contributions presented in this study can be found in online repositories, including the article and supplementary material. Further inquiries can be directed to the corresponding author.
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Data availability statement
Data are available in a public, open access repository. The original contributions presented in this study can be found in online repositories, including the article and supplementary material. Further inquiries can be directed to the corresponding author.
Footnotes
Contributors XK designed this study. DNA extraction and nanopore sequencing were performed by YW and ZZ. Bioinformatic analyses were conducted by YW and FM. SNP linkage analysis was completed by YW and ZZ. YW wrote the manuscript, and all authors discussed the results, revised the manuscript and approved the submission. XK was the guarantor.
Funding This work was supported by the Henan Province Medical Science and Technique Foundation (SBGJ202102097), the Henan Province Fertility Protection and Eugenics Key Laboratory Open Project (SYLBHHYS2022-02), the Guangxi Key Laboratory of Birth Defects Open Project (GXWCH-ZDKF-2022-05) and the Natural Science Foundation of Henan Province (242300420400).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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