TY - JOUR T1 - Chromosome 10q-linked FSHD identifies <em>DUX4</em> as principal disease gene JF - Journal of Medical Genetics JO - J Med Genet SP - 180 LP - 188 DO - 10.1136/jmedgenet-2020-107041 VL - 59 IS - 2 AU - Richard J L F Lemmers AU - Patrick J van der Vliet AU - Ana Blatnik AU - Judit Balog AU - Janez Zidar AU - Don Henderson AU - Rianne Goselink AU - Stephen J Tapscott AU - Nicol C Voermans AU - Rabi Tawil AU - George W A M Padberg AU - Baziel GM van Engelen AU - Silvère M van der Maarel Y1 - 2022/02/01 UR - http://jmg.bmj.com/content/59/2/180.abstract N2 - 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.All data relevant to the study are included in the article or uploaded as supplementary information. ER -