Facioscapulohumeral muscular dystrophy

Statland, Jeffrey; Tawil, Rabi

doi:10.1097/wco.0b013e32834959af

Cited by 54 publications

(26 citation statements)

References 59 publications

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“…One of the most intriguing clinical observations in FSHD is the marked inter- and intrafamilial variability in disease onset and progression [46]. While one-fifth of FSHD1 patients will become wheelchair dependent, an equal proportion of FSHD1 mutation carriers are asymptomatic but minimally affected on examination [47].…”

Section: Balancing Between Genetic and Epigenetic Factorsmentioning

confidence: 99%

Genetic and epigenetic contributors to FSHD

Daxinger

Tapscott

Maarel

2015

Current Opinion in Genetics & Development

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Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscle disorder characterized by distinct chromatin changes including DNA hypomethylation of the D4Z4 macrosatellite repeat array on a disease-permissive 4qA allele and aberrant expression of the D4Z4-embedded DUX4 retrogene in skeletal muscle. Insufficient epigenetic repression of the D4Z4 repeat is the result of at least two different genetic mechanisms leading to two forms of disease, FSHD1 and FSHD2. In the case of FSHD1, a contraction of the D4Z4 repeat array is disease causing whereas FSHD2 is most often caused by mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene. Recent studies indicate that a combination of genetic and epigenetic factors that act on the D4Z4 repeat array determine the probability of DUX4 expression in skeletal muscle and disease penetrance and progression.

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Section: Balancing Between Genetic and Epigenetic Factorsmentioning

confidence: 99%

Genetic and epigenetic contributors to FSHD

Daxinger

Tapscott

Maarel

2015

Current Opinion in Genetics & Development

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“…For example, the promoter expansions of the CGG repeat that causes Fragile X are associated with silencing of FMR1 via hypermethylation [39]. On a larger scale, contractions of the D4Z4 macrosatellite that contains the DUX4 gene, in combination with a permissive haplotype background, underlie facioscapulohumeral muscular dystrophy (FSHD) [reviewed in 40]. Reduced D4Z4 copy number is associated with a loss of DNA local methylation and heterochromatic histone marks [41], and is accompanied by an upregulation of local gene expression, although the mechanism causing this is unclear [42].…”

Section: Introductionmentioning

confidence: 99%

Digital Genotyping of Macrosatellites and Multicopy Genes Reveals Novel Biological Functions Associated with Copy Number Variation of Large Tandem Repeats

et al. 2014

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Tandem repeats are common in eukaryotic genomes, but due to difficulties in assaying them remain poorly studied. Here, we demonstrate the utility of Nanostring technology as a targeted approach to perform accurate measurement of tandem repeats even at extremely high copy number, and apply this technology to genotype 165 HapMap samples from three different populations and five species of non-human primates. We observed extreme variability in copy number of tandemly repeated genes, with many loci showing 5–10 fold variation in copy number among humans. Many of these loci show hallmarks of genome assembly errors, and the true copy number of many large tandem repeats is significantly under-represented even in the high quality ‘finished’ human reference assembly. Importantly, we demonstrate that most large tandem repeat variations are not tagged by nearby SNPs, and are therefore essentially invisible to SNP-based GWAS approaches. Using association analysis we identify many cis correlations of large tandem repeat variants with nearby gene expression and DNA methylation levels, indicating that variations of tandem repeat length are associated with functional effects on the local genomic environment. This includes an example where expansion of a macrosatellite repeat is associated with increased DNA methylation and suppression of nearby gene expression, suggesting a mechanism termed “repeat induced gene silencing”, which has previously been observed only in transgenic organisms. We also observed multiple signatures consistent with altered selective pressures at tandemly repeated loci, suggesting important biological functions. Our studies show that tandemly repeated loci represent a highly variable fraction of the genome that have been systematically ignored by most previous studies, copy number variation of which can exert functionally significant effects. We suggest that future studies of tandem repeat loci will lead to many novel insights into their role in modulating both genomic and phenotypic diversity.

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“…Recent data suggest a unified pathogenic model of FSHD [19]. The symptoms of FSHD include a distinctive pattern of muscle weakness that affects facial and scapular fixator muscles [3,20,21]. Muscle wasting often progresses slowly and typically in a descending pattern to include distal anterior leg and hip girdle muscles.…”

Section: Introductionmentioning

confidence: 99%

If you build a rare disease registry, will they enroll and will they use it? Methods and data from the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD)

Hilbert

Kissel²,

Luebbe

et al. 2012

Contemporary Clinical Trials

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Introduction Registries are becoming increasingly important for rare diseases as experimental therapies develop. This report describes the methodology behind the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD) Patients and Family Members to facilitate the development of other rare disease registries. We also highlight data about the pathophysiology and select burdens of DM and FSHD reported at baseline and longitudinally. Methods The Registry consists of de-identified, patient reported information collected at baseline and annually and information from review of medical records. Investigators can use the Registry to analyze de-identified data and to facilitate recruitment into clinical studies. Results To date, the Registry has enrolled 1611 members, facilitated 24 studies, and collected data annually for up to 8 years. Genetic test results were obtained in 56.2% of enrollees. Approximately one-third of members used assistive devices and another one-third reported psychological problems at baseline. Wheelchair use was reported for both short and long distances by 7.0% of DM and 18.1% of FSHD members. Approximately 60% of members reported their employment was affected by their disease. Conclusions Strengths of the Registry include large sample sizes, stringent review of clinical and molecular data, annually updated information, and regular interactions between patients and investigators. Registry data provide new insights into the burdens of DM and FSHD, such as, psychological problems and reduced employment. Opportunities abound for investigators to utilize Registry resources to assess the impact of these and other burdens on health care costs, progression of symptoms, and quality of life.

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Facioscapulohumeral muscular dystrophy

Cited by 54 publications

References 59 publications

Genetic and epigenetic contributors to FSHD

Genetic and epigenetic contributors to FSHD

Digital Genotyping of Macrosatellites and Multicopy Genes Reveals Novel Biological Functions Associated with Copy Number Variation of Large Tandem Repeats

If you build a rare disease registry, will they enroll and will they use it? Methods and data from the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD)

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