Comprehensive genetic analysis of facioscapulohumeral muscular dystrophy by Nanopore long-read whole-genome sequencing

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Abstract

Background

Facioscapulohumeral muscular dystrophy (FSHD) is a high-prevalence autosomal dominant neuromuscular disease characterized by significant clinical and genetic heterogeneity. Genetic diagnosis of FSHD remains a challenge because it cannot be detected by standard sequencing methods and requires a complex diagnosis workflow.

Methods

We developed a comprehensive genetic FSHD detection method based on Oxford Nanopore Technologies (ONT) whole-genome sequencing. Using a case–control design, we applied this procedure to 29 samples and compared the results with those from optical genome mapping (OGM), bisulfite sequencing (BSS), and whole-exome sequencing (WES).

Results

Using our ONT-based method, we identified 59 haplotypes (35 4qA and 24 4qB) among the 29 samples (including a mosaic sample), as well as the number of D4Z4 repeat units (RUs). The pathogenetic D4Z4 RU contraction identified by our ONT-based method showed 100% concordance with OGM results. The methylation levels of the most distal D4Z4 RU and the double homeobox 4 gene ( DUX4) detected by ONT sequencing are highly consistent with the BSS results and showed excellent diagnostic efficiency. Additionally, our ONT-based method provided an independent methylation profile analysis of two permissive 4qA alleles, reflecting a more accurate scenario than traditional BSS. The ONT-based method detected 17 variations in three FSHD2-related genes from nine samples, showing 100% concordance with WES.

Conclusions

Our ONT-based FSHD detection method is a comprehensive method for identifying pathogenetic D4Z4 RU contractions, methylation level alterations, allele-specific methylation of two 4qA haplotypes, and variations in FSHD2-related genes, which will all greatly improve genetic testing for FSHD.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-024-05259-8.

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Most cited references 33

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Detecting DNA cytosine methylation using nanopore sequencing

Jared Simpson, Rachael E. Workman, P C Zuzarte … (2017)

A hidden Markov model (HMM)-based tool enables detection of 5-methylcytosine (5-mC) from single-molecule nanopore-sequencing data generated directly from human genomic DNA without chemical treatment.

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Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy.

C Wijmenga, J E Hewitt, L Sandkuijl … (1992)

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder which maps to chromosome 4qter, distal to the D4S139 locus. The cosmid clone 13E, isolated in a search for homeobox genes, was subsequently mapped to 4q35, also distal to D4S139. A subclone, p13E-11, detects in normal individuals a polymorphic EcoRI fragment usually larger than 28 kilobases (kb). Surprisingly, using the same probe we detected de novo DNA rearrangements, characterized by shorter EcoRI fragments (14-28 kb), in 5 out of 6 new FSHD cases. In 10 Dutch families analysed, a specific shorter fragment between 14-28 kb cosegregates with FSHD. Both observations indicate that FSHD is caused by independent de novo DNA rearrangements in the EcoRI fragment detected by p13E-11.

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Population-based incidence and prevalence of facioscapulohumeral dystrophy.

J. J. G. M. Verschuuren, Marc Van Ranst, J. Verbeek … (2014)

To determine the incidence and prevalence of facioscapulohumeral muscular dystrophy (FSHD) in the Netherlands. Using 3-source capture-recapture methodology, we estimated the total yearly number of newly found symptomatic individuals with FSHD, including those not registered in any of the 3 sources. To this end, symptomatic individuals with FSHD were available from 3 large population-based registries in the Netherlands if diagnosed within a 10-year period (January 1, 2001 to December 31, 2010). Multiplication of the incidence and disease duration delivered the prevalence estimate. On average, 52 people are newly diagnosed with FSHD every year. This results in an incidence rate of 0.3/100,000 person-years in the Netherlands. The prevalence rate was 12/100,000, equivalent to 2,000 affected individuals. We present population-based incidence and prevalence estimates regarding symptomatic individuals with FSHD, including an estimation of the number of symptomatic individuals not present in any of the 3 used registries. This study shows that the total number of symptomatic persons with FSHD in the population may well be underestimated and a considerable number of affected individuals remain undiagnosed. This suggests that FSHD is one of the most prevalent neuromuscular disorders. © 2014 American Academy of Neurology.

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Author and article information

Contributors

Yan Wang: wangyan@njmu.edu.cn

Zhengfeng Xu: zhengfengxu@njmu.edu.cn

Ping Hu:

ORCID: http://orcid.org/0000-0002-7297-8847

njfybjyhuping@163.com

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 13 May 2024

Publication date PMC-release: 13 May 2024

Publication date Collection: 2024

Volume: 22

Electronic Location Identifier: 451

Affiliations

[1 ]Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University, Nanjing Women and Children’s Healthcare Hospital, ( https://ror.org/059gcgy73) 123 Tianfei Alley, Mochou Road, Nanjing, Jiangsu 210004 People’s Republic of China

[2 ]Department of Neurology, Nanjing First Hospital, Nanjing Medical University, ( https://ror.org/059gcgy73) Nanjing, Jiangsu 210006 People’s Republic of China

Author information

Ping Hu http://orcid.org/0000-0002-7297-8847

Article

Publisher ID: 5259

DOI: 10.1186/s12967-024-05259-8

PMC ID: 11092085

PubMed ID: 38741136

SO-VID: c7a0a014-8959-4876-a165-22969c09182a

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 10 December 2023

Date accepted : 29 April 2024

Funding

Funded by: National Key R& D Program of China

Award ID: 2022YFC2703400

Award ID: 2021YFC1005301

Award Recipient : Zhengfeng Xu Ping Hu

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81971398

Award ID: 82101943

Award ID: 82103927

Award Recipient : Mingtao Huang Qinxin Zhang Ping Hu

Funded by: FundRef http://dx.doi.org/10.13039/501100004608, Natural Science Foundation of Jiangsu Province;

Award ID: BK20210037

Award Recipient : Mingtao Huang

Funded by: Jiangsu Province Capability Improvement Project through Science, Technology, and Education Jiangsu Provincial Medical Key Discipline

Award ID: ZDXK202211

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: facioscapulohumeral muscular dystrophy,long-read sequencing,whole genome sequencing,methylation,single nucleotide variant

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ScienceOpen disciplines: Medicine

Keywords: facioscapulohumeral muscular dystrophy, long-read sequencing, whole genome sequencing, methylation, single nucleotide variant

Comprehensive genetic analysis of facioscapulohumeral muscular dystrophy by Nanopore long-read whole-genome sequencing

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

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Arabidopsis genomics

Most cited references 33

Detecting DNA cytosine methylation using nanopore sequencing

Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy.

Population-based incidence and prevalence of facioscapulohumeral dystrophy.

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