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Neurogenetics
Original research
Chromosome 10q-linked FSHD identifies DUX4 as principal disease gene
  1. Richard J L F Lemmers1,
  2. Patrick J van der Vliet1,
  3. Ana Blatnik2,
  4. Judit Balog1,
  5. Janez Zidar3,
  6. Don Henderson4,
  7. Rianne Goselink5,
  8. Stephen J Tapscott6,
  9. Nicol C Voermans5,
  10. Rabi Tawil4,
  11. George W A M Padberg5,
  12. Baziel GM van Engelen5,
  13. Silvère M van der Maarel1
  1. 1 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
  2. 2 Cancer Genetics Clinic, Institute of Oncology, Ljubljana, Slovenia
  3. 3 Division of Neurology, Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia
  4. 4 Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA
  5. 5 Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
  6. 6 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  1. Correspondence to Dr Richard J L F Lemmers, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands; r.j.l.f.lemmers{at}lumc.nl

Abstract

Background Facioscapulohumeral dystrophy (FSHD) is an inherited muscular dystrophy clinically characterised by muscle weakness starting with the facial and upper extremity muscles. A disease model has been developed that postulates that failure in somatic repression of the transcription factor DUX4 embedded in the D4Z4 repeat on chromosome 4q causes FSHD. However, due to the position of the D4Z4 repeat close to the telomere and the complex genetic and epigenetic aetiology of FSHD, there is ongoing debate about the transcriptional deregulation of closely linked genes and their involvement in FSHD.

Method Detailed genetic characterisation and gene expression analysis of patients with clinically confirmed FSHD and control individuals.

Results Identification of two FSHD families in which the disease is caused by repeat contraction and DUX4 expression from chromosome 10 due to a de novo D4Z4 repeat exchange between chromosomes 4 and 10. We show that the genetic lesion causal to FSHD in these families is physically separated from other candidate genes on chromosome 4. We demonstrate that muscle cell cultures from affected family members exhibit the characteristic molecular features of FSHD, including DUX4 and DUX4 target gene expression, without showing evidence for transcriptional deregulation of other chromosome 4-specific candidate genes.

Conclusion This study shows that in rare situations, FSHD can occur on chromosome 10 due to an interchromosomal rearrangement with the FSHD locus on chromosome 4q. These findings provide further evidence that DUX4 derepression is the dominant disease pathway for FSHD. Hence, therapeutic strategies should focus on DUX4 as the primary target.

  • gene rearrangement
  • neuromuscular diseases
  • gene expression
  • diagnosis
  • genetic research

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/jmedgenet-2020-107041

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • Contributors RJLFL and SMvdM contributed to the study design and conception of study. RJLFL, PJvdV, AB, JB, JZ, DH, RJMG, NV, RT, GP, BvE contributed to the data collection and assembly. RJLFL and PJvdV contributed to the data analysis and interpretation. RJLFL and SMvdM contributed to the writing of manuscript. RJLFL, PJvdV, JB, SJT, NV, GP and SMvdM critical reviewed and revised the manuscript. RJLFL submitted the manuscript.

    • Funding This work was supported by funds from the National Institute of Neurological Disorders and Stroke grant number P01NS069539, the Prinses Beatrix Spierfonds grant numbers W.OP14-01 and W.OB17-01 and Spieren voor Spieren.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.