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
- genetic research
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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.
Patient consent for publication Obtained.
Ethics approval This study protocol has been approved by the Medical Review Ethics Committee region Arnhem-Nijmegen (NL53213.091.15) and was conducted according to the criteria set by the declaration of Helsinki and its later amendments.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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