ArticleEuropean journal of human genetics : EJHG2018
Deep characterization of a common D4Z4 variant identifies biallelic DUX4 expression as a modifier for disease penetrance in FSHD2.
Article in European journal of human genetics : EJHG, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 31 citations in OpenAlex.
- Nanopore Ultra-Long Sequencing for FSHD: From Molecular Diagnosis to Preimplantation Genetic Testing.Genes · 2026Review
- Complete genetic and epigenetic architecture of D4Z4 macrosatellites in FSHD, BAMS, and reference cohorts with D4Z4End2End.Genome research · 2026Article
- Nuclear Protein Aggregates Disrupt RNA Processing and Alter Biomechanics in a Muscle Cell Model of OPMD.Aging and disease · 2025Article
- Polyalanine Expansion in PABPN1 Alters the Structure and Dynamics of Its Nuclear Aggregates in Differentiated Muscle Cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- The first genetically confirmed cohort of Facioscapulohumeral Muscular Dystrophy from Northern India.European journal of human genetics : EJHG · 2024Article
- Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines.Clinical genetics · 2024Review
- Comprehensive genetic analysis of facioscapulohumeral muscular dystrophy by Nanopore long-read whole-genome sequencing.Journal of translational medicine · 2024Article
- Autosomal dominant in cis D4Z4 repeat array duplication alleles in facioscapulohumeral dystrophy.Brain : a journal of neurology · 2024Article
- Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy in Patients Clinically Suspected of FSHD Using Optical Genome Mapping.Neurology. Genetics · 2023Article
- Deciphering D4Z4 CpG methylation gradients in fascioscapulohumeral muscular dystrophy using nanopore sequencing.Genome research · 2023Article
- High-resolution breakpoint junction mapping of proximally extended D4Z4 deletions in FSHD1 reveals evidence for a founder effect.Human molecular genetics · 2022Article
- Chromosome 10q-linked FSHD identifiesJournal of medical genetics · 2022Article
- Considerations and practical implications of performing a phenotypic CRISPR/Cas survival screen.PloS one · 2022Article
- Adenine base editing of theMolecular therapy. Nucleic acids · 2021Article
- Facioscapulohumeral muscular dystrophy: genetics, gene activation and downstream signalling with regard to recent therapeutic approaches: an update.Orphanet journal of rare diseases · 2021Review
- Review
- Consequences of epigenetic derepression in facioscapulohumeral muscular dystrophy.Clinical genetics · 2020Review
- Single-molecule optical mapping enables quantitative measurement of D4Z4 repeats in facioscapulohumeral muscular dystrophy (FSHD).Journal of medical genetics · 2020Article
- Scapular dyskinesis in myotonic dystrophy type 1: clinical characteristics and genetic investigations.Journal of neurology · 2019Observational
- FSHD1 and FSHD2 form a disease continuum.Neurology · 2019Article
Corrections and comments
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Authors and funding
17 authors at 6 institutions in 3 countries.
Funding
Abstract
Facioscapulohumeral muscular dystrophy is caused by incomplete repression of the transcription factor DUX4 in skeletal muscle as a consequence of D4Z4 macrosatellite repeat contraction in chromosome 4q35 (FSHD1) or variants in genes encoding D4Z4 chromatin repressors (FSHD2). A clinical hallmark of FSHD is variability in onset and progression suggesting the presence of disease modifiers. A well-known cis modifier is the polymorphic DUX4 polyadenylation signal (PAS) that defines FSHD permissive alleles: D4Z4 chromatin relaxation on non-permissive alleles which lack the DUX4-PAS cannot cause disease in the absence of stable DUX4 mRNA. We have explored the nature and relevance of a common variant of the major FSHD haplotype 4A161, which is defined by 1.6 kb size difference of the most distal D4Z4 repeat unit. While the short variant (4A161S) has been extensively studied, we demonstrate that the long variant (4A161L) is relatively common in the European population, is capable of expressing DUX4, but that DUX4 mRNA processing differs from 4A161S. While we do not find evidence for a difference in disease severity between FSHD carriers of an 4A161S or 4A161L allele, our study does uncover biallelic DUX4 expression in FSHD2 patients. Compared to control individuals, we observed an increased frequency of FSHD2 patients homozygous for disease permissive alleles, and who are thus capable of biallelic DUX4 expression, while SMCHD1 variant carriers with only one permissive allele were significantly more often asymptomatic. This suggests that biallelic DUX4 expression lowers the threshold for disease presentation and is a modifier for disease severity in FSHD2.
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