Autosomal dominant in cis D4Z4 repeat array duplication alleles in facioscapulohumeral dystrophy
Brain, vol. 147, pp. 414–426
Abstract
Facioscapulohumeral dystrophy (FSHD) has a unique genetic aetiology resulting in partial chromatin relaxation of the D4Z4 macrosatellite repeat array on 4qter. This D4Z4 chromatin relaxation facilitates inappropriate expression of the transcription factor DUX4 in skeletal muscle. DUX4 is encoded by a retrogene that is embedded within the distal region of the D4Z4 repeat array. In the European population, the D4Z4 repeat array is usually organized in a single array that ranges between 8 and 100 units. D4Z4 chromatin relaxation and DUX4 derepression in FSHD is most often caused by repeat array contraction to 1-10 units (FSHD1) or by a digenic mechanism requiring pathogenic variants in a D4Z4 chromatin repressor like SMCHD1, combined with a repeat array between 8 and 20 units (FSHD2). With a prevalence of 1.5% in the European population, in cis duplications of the D4Z4 repeat array, where two adjacent D4Z4 arrays are interrupted by a spacer sequence, are relatively common but their relationship to FSHD is not well understood. In cis duplication alleles were shown to be pathogenic in FSHD2 patients; however, there is inconsistent evidence for the necessity of an SMCHD1 mutation for disease development. To explore the pathogenic nature of these alleles we compared in cis duplication alleles in FSHD patients with or without pathogenic SMCHD1 variant. For both groups we showed duplication-allele-specific DUX4 expression. We studied these alleles in detail using pulsed-field gel electrophoresis-based Southern blotting and molecular combing, emphasizing the challenges in the characterization of these rearrangements. Nanopore sequencing was instrumental to study the composition and methylation of the duplicated D4Z4 repeat arrays and to identify the breakpoints and the spacer sequence between the arrays. By comparing the composition of the D4Z4 repeat array of in cis duplication alleles in both groups, we found that specific combinations of proximal and distal repeat array sizes determine their pathogenicity. Supported by our algorithm to predict pathogenicity, diagnostic laboratories should now be furnished to accurately interpret these in cis D4Z4 repeat array duplications, alleles that can easily be missed in routine settings.
Authors 23
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center , 2300 RC, Leiden , The Netherlands
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Affiliation as printed
Department of Pediatrics, University of Utah , Salt Lake City, UT 84112 , USA
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center , 2300 RC, Leiden , The Netherlands
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Affiliation as printed
Department of Neurology, University Hospital , 9000 Gent , Belgium
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University Medical Center Utrecht
Affiliation as printed
University Medical Center Utrecht , 3584 EA, Utrecht , The Netherlands
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Affiliation as printed
Department of Human Genetics, University of Utah , Salt Lake City, UT 84112 , USA
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Radboud University Medical Center
Affiliation as printed
Neuromuscular Centre Nijmegen, Radboud University Nijmegen Medical Centre , 6525 GA, Nijmegen , The Netherlands
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Affiliation as printed
Department of Neurology, Algemeen Ziekenhuis Sint-Jan , 8000, Brugge , Belgium
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Affiliation as printed
Department of Neurology, Algemeen Ziekenhuis Sint-Jan , 8000, Brugge , Belgium
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center , 2300 RC, Leiden , The Netherlands
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Inserm · Sorbonne Université · Institut de Myologie · Centre de Recherche en Myologie
Affiliation as printed
Sorbonne Université, Inserm UMRS974, Institut de Myologie, Centre de Recherche en Myologie , F-75013 Paris , France
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Radboud University Medical Center
Affiliation as printed
Neuromuscular Centre Nijmegen, Radboud University Nijmegen Medical Centre , 6525 GA, Nijmegen , The Netherlands
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University of Kansas Medical Center
Affiliation as printed
University of Kansas Medical Center , Kansas City, KS 66103 , USA
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National Hospital for Neurology and Neurosurgery · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
National Hospital For Neurology and Neurosurgery, UCL Queen Square Institute of Neurology , London, WC1N 3BG , UK
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center , 2300 RC, Leiden , The Netherlands
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Assistance Publique – Hôpitaux de Paris · Institut de Myologie
Affiliation as printed
Unité de Morphologie Neuromusculaire, Institut de Myologie, AP-HP , F-75013, Paris , France
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Affiliation as printed
The John Walton Muscular Dystrophy Research Centre , Faculty of Medical Sciences, Newcastle upon Tyne, NE1 3BZ , UK
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Cliniques Universitaires Saint-Luc
Affiliation as printed
Department of Neurology, Saint-Luc UCL , 1200, Brussels , Belgium
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University of Rochester Medicine
Affiliation as printed
Department of Neurology, University of Rochester Medical Center , NY 14642, Rochester , USA
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Radboud University Medical Center
Affiliation as printed
Neuromuscular Centre Nijmegen, Radboud University Nijmegen Medical Centre , 6525 GA, Nijmegen , The Netherlands
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Affiliation as printed
Department of Neurology, University of Copenhagen , DK-2100 Copenhagen , Denmark
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Affiliation as printed
Department of Human Genetics, University of Utah , Salt Lake City, UT 84112 , USA
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center , 2300 RC, Leiden , The Netherlands
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Cited by patents worldwide 1 (Lens.org)
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