Facioscapulohumeral muscular dystrophy type 2: an update on the clinical, genetic, and molecular findings

Jia, Fangzhi; Drew, Alexander P.; Nicholson, Garth A.; Corbett, Alastair; Kumar, Kishore R.

doi:10.1016/j.nmd.2021.09.010

Cited by 12 publications

(13 citation statements)

References 123 publications

(177 reference statements)

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“…In addition, the presence of subtelomeric variants of the 4q (namely, 4qA or permissive allele) have been associated with FSHD [ 1 ]. Furthermore, detrimental variants in SMCHD1 , LRIF1 and DNMT3B have been described as causative genes (i.e., FSHD2) or disease modifiers with or without the presence of DRA [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Moreover, the above-mentioned genetic alterations were associated with epigenetic changes at the D4Z4 locus, such as DNA hypomethylation that has been reported to contribute to FSHD [ 1 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

D4Z4 Methylation Levels Combined with a Machine Learning Pipeline Highlight Single CpG Sites as Discriminating Biomarkers for FSHD Patients

Caputo

Megalizzi

Fabrizio

et al. 2022

Cells

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The study describes a protocol for methylation analysis integrated with Machine Learning (ML) algorithms developed to classify Facio-Scapulo-Humeral Dystrophy (FSHD) subjects. The DNA methylation levels of two D4Z4 regions (DR1 and DUX4-PAS) were assessed by an in-house protocol based on bisulfite sequencing and capillary electrophoresis, followed by statistical and ML analyses. The study involved two independent cohorts, namely a training group of 133 patients with clinical signs of FSHD and 150 healthy controls (CTRL) and a testing set of 27 FSHD patients and 25 CTRL. As expected, FSHD patients showed significantly reduced methylation levels compared to CTRL. We utilized single CpG sites to develop a ML pipeline able to discriminate FSHD subjects. The model identified four CpGs sites as the most relevant for the discrimination of FSHD subjects and showed high metrics values (accuracy: 0.94, sensitivity: 0.93, specificity: 0.96). Two additional models were developed to differentiate patients with lower D4Z4 size and patients who might carry pathogenic variants in FSHD genes, respectively. Overall, the present model enables an accurate classification of FSHD patients, providing additional evidence for DNA methylation as a powerful disease biomarker that could be employed for prioritizing subjects to be tested for FSHD.

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Section: Introductionmentioning

confidence: 99%

D4Z4 Methylation Levels Combined with a Machine Learning Pipeline Highlight Single CpG Sites as Discriminating Biomarkers for FSHD Patients

Caputo

Megalizzi

Fabrizio

et al. 2022

Cells

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“…Of note, at least 1 D4Z4 repeat is required to develop FSHD and an absence of the 4q telomeric region was observed in phenotypically normal cases (Tupler et al, 1996). In the remaining 5% of FSHD patients (FSHD2, OMIM: 158,901), mutations in epigenetic modifier genes including SMCHD1, DNMT3B or LRIF1, a known SMCHD1 protein interactor, have been reported (Figure 2) (Lemmers et al, 2012;van den Boogaard et al, 2016;Hamanaka et al, 2020;Jia et al, 2021). FSHD1 and FSHD2 are clinically undistinguishable (de Greef et al, 2010) and despite the fact that FSDH1 and 2 do not carry the same mutation, they both lead to chromatin relaxation and to the aberrant expression the DUX4 gene.…”

Section: Facioscapulohumeral Muscular Dystrophymentioning

confidence: 99%

Gene Editing to Tackle Facioscapulohumeral Muscular Dystrophy

Mariot

Dumonceaux²

2022

Front. Genome Ed.

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Facioscapulohumeral dystrophy (FSHD) is a skeletal muscle disease caused by the aberrant expression of the DUX4 gene in the muscle tissue. To date, different therapeutic approaches have been proposed, targeting DUX4 at the DNA, RNA or protein levels. The recent development of the clustered regularly interspaced short-palindromic repeat (CRISPR) based technology opened new avenues of research, and FSHD is no exception. For the first time, a cure for genetic muscular diseases can be considered. Here, we describe CRISPR-based strategies that are currently being investigated for FSHD. The different approaches include the epigenome editing targeting the DUX4 gene and its promoter, gene editing targeting the polyadenylation of DUX4 using TALEN, CRISPR/cas9 or adenine base editing and the CRISPR-Cas9 genome editing for SMCHD1. We also discuss challenges facing the development of these gene editing based therapeutics.

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“…The disease is caused by the toxic expression of the DUX4, a retrogene contained in every D4Z4 macrosatellite repeat array on chromosome 4q35, expressed in the germline but typically repressed in somatic tissue. The derepression of the DUX4 occurs from an opening of the chromatin structure either by contraction of the number of repeats (FSHD1) or by chromatin hypomethylation of the D4Z4 repeats stemming from mutations in SMCHD1, DNMT3B and LRIF1, genes involved in chromatin methylation (FSHD2) [ 11 , 12 , 13 , 14 , 15 ]. Individuals suffering from FSHD1 carry a reduced number of 1 to 10 D4Z4 repeats (each 3.3 kb), while non patients carry a number of 11 to 100 repeats.…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies showed that the human retrogene DUX4 activates target genes such as PAX7 that are proposed to drive muscular dystrophy pathology in a toxic gain-of-function model [ 17 ]. Moreover, the FSHD2 subtype seems to arise through a common to FSHD1 downstream mechanism of epigenetic derepression including the epigenetic modifier of D4Z4 repression DNMT3B and LRIF1 [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Orofacial Muscle Weakening in Facioscapulohumeral Muscular Dystrophy (FSHD) Patients

et al. 2022

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Background: Facioscapulohumeral muscular dystrophy is the third most commonly found type of muscular dystrophy. The aim of this study was to correlate the D4Z4 repeat array fragment size to the orofacial muscle weakening exhibited in a group of patients with a genetically supported diagnosis of FSHD. Methods: Molecular genetic analysis was performed for 52 patients (27 female and 25 male) from a group that consisted of 36 patients with autosomal dominant pedigrees and 16 patients with either sporadic or unknown family status. The patients were tested with the southern blotting technique, using EcoRI/Avrll double digestion, and fragments were detected by a p13E-11 telomeric probe. Spearman’s correlation was used to compare the fragment size with the degree of muscle weakening found in the forehead, periocular and perioral muscles. Results: A positive non-significant correlation between the DNA fragment size and severity of muscle weakness was found for the forehead (r = 0.27; p = 0187), the periocular (r = 0.24; p = 0.232) and the left and right perioral (r = 0.29; p = 0.122), (r = 0.32; p = 0.085) muscles. Conclusions: Although FSHD patients exhibited a decrease in muscular activity related to the forehead, perioral, and periocular muscles the genotype–phenotype associations confirmed a weak to moderate non-significant correlation between repeat size and the severity of muscle weakness. Orofacial muscle weakening and its association with a D4Z4 contraction alone may not have the significance to serve as a prognostic biomarker, due to the weak to moderate association. Further studies with larger sample sizes are needed to determine the degree of genetic involvement in the facial growth in FSHD patients.

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Facioscapulohumeral muscular dystrophy type 2: an update on the clinical, genetic, and molecular findings

Cited by 12 publications

References 123 publications

D4Z4 Methylation Levels Combined with a Machine Learning Pipeline Highlight Single CpG Sites as Discriminating Biomarkers for FSHD Patients

D4Z4 Methylation Levels Combined with a Machine Learning Pipeline Highlight Single CpG Sites as Discriminating Biomarkers for FSHD Patients

Gene Editing to Tackle Facioscapulohumeral Muscular Dystrophy

Orofacial Muscle Weakening in Facioscapulohumeral Muscular Dystrophy (FSHD) Patients

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