Large-Scale Population Analysis Challenges the Current Criteria for the Molecular Diagnosis of Fascioscapulohumeral Muscular Dystrophy

Scionti, Isabella; Greco, Francesca; Ricci, Giulia; Govi, Monica; Arashiro, Patricia; Vercelli, Liliana; Berardinelli, Angela; Angelini, C.; Antonini, Giovanni; Cao, Michelangelo; Muzio, Antonio Di; Moggio, Maurizio; Morandi, Lucia; Ricci, Enzo; Rodolico, Carmelo; Ruggiero, Lucia; Santoro, Lucio; Siciliano, Gabriele; Tomelleri, Giuliano; Trevisan, Carlo P.; Galluzzi, G.; Wright, Woodring E.; Zatz, Mayana; Tupler, Rossella

doi:10.1016/j.ajhg.2012.02.019

Cited by 107 publications

(141 citation statements)

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“…The genotype-phenotype correlation conducted more recently on a large scale using a standardized method of evaluation allowed to estimate that 1) 20% of FSHD patients carry full-length D4Z4 alleles, 2) over 25% of relatives carrying D4Z4 reduced alleles do not have FSHD, 3) 3% of healthy subjects from the general population carry D4Z4 reduced alleles 4) no specific 4q haplotype is uniquely associated with FSHD. Remarkably, these studies established as a general rule rather than an exception that detection of a D4Z4 reduced allele is not sufficient to predict FSHD (Scionti et al, 2012a;Scionti et al, 2012b). Over the years, the molecular etiology of FSHD has remained enigmatic, and the literature is filled with claims of causes that fail to be confirmed by other groups.…”

Section: Discussionmentioning

confidence: 98%

“…These findings seems to indicate that in a substantial proportion of 38 to 45 kb-sized repeat arrays penetrance may be close to zero, but in some families 38−45 kb alleles are associated with myopathy (Butz et al, 2003). Remarkably D4Z4 repeat array of size between 21-34 kb (4-8 repeats) were found in 3% of 801 Italian and Brazilian samples of normal individuals unrelated to any FSHD patients, indicating that in this size-range, additional factors influence the disease expression (Scionti et al, 2012b). In conclusion the high variability in clinical expression makes difficult to establish a prognostic correlation between the number of the D4Z4 repeats and the severity of the disease.…”

Section: Severity Of the Disease And Repeats Number: Does A Linear Comentioning

confidence: 96%

“…Second, characterization of 253 unrelated FSHD probands from the Italian National Registry for FSHD showed that only 127 of them (50.1%) carry D4Z4 alleles with 1-8 D4Z4 associated with 4A161PAS, whereas the remaining FSHD probands carry different haplotypes or alleles with greater number of D4Z4 repeats (Scionti et al, 2012b). Third, molecular analysis of 801 normal healthy subjects from Italy and Brazil showed that that 3% of individuals from the general population carry alleles with reduced number (4-8) of D4Z4 repeats on chromosome 4q and one third of these alleles occurs in combination with the 4A161PAS haplotype (Scionti et al, 2012b) All these findings challenge the hypothesis that 4APAS structure is necessary and sufficient for the development of FSHD. This discovery is not incompatible with evidence implicating DUX4 or other factors as important mediators of disease.…”

Section: Permissive and Non-permissive Genetic Backgroundmentioning

confidence: 99%

“…Most importantly it has been recently showed that the polymorphism adding the polyadenylation signal to DUX4 RNA, is common in the general population. Thus, just a portion of subjects carrying this molecular signature develops FSHD (Scionti et al, 2012b). Consequently, the number of D4Z4 repeats at 4q35 by itself or in association with a specific haplotype, does not to fully explain FSHD development.…”

Section: Introductionmentioning

confidence: 99%

“…For example, several studies described FSHD patients carrying full-length D4Z4 alleles that are clinically indistinguishable from FSHD subjects carrying D4Z4 reduced alleles. Conversely, there is a high percent of normal individuals, unrelated to any FSHD patients, with reduced D4Z4 alleles (Scionti et al, 2012b). Most importantly it has been recently showed that the polymorphism adding the polyadenylation signal to DUX4 RNA, is common in the general population.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Facioscapulohumeral Muscular Dystrophy: From Clinical Data to Molecular Genetics and Return

Salani¹,

Morini²,

Scionti³

et al. 2012

Neuromuscular Disorders

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Section: Discussionmentioning

confidence: 98%

Section: Severity Of the Disease And Repeats Number: Does A Linear Comentioning

confidence: 96%

Section: Permissive and Non-permissive Genetic Backgroundmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Facioscapulohumeral Muscular Dystrophy: From Clinical Data to Molecular Genetics and Return

Salani¹,

Morini²,

Scionti³

et al. 2012

Neuromuscular Disorders

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Phenotypic Variability Among Patients With D4Z4 Reduced Allele Facioscapulohumeral Muscular Dystrophy

Ruggiero¹,

Mele

Manganelli³

et al. 2020

JAMA Netw Open

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IMPORTANCE Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disorder, associated with the deletion of tandemly arrayed D4Z4 repetitive elements. The extensive use of molecular analysis of the D4Z4 locus for FSHD diagnosis has revealed wide clinical variability, suggesting that subgroups of patients exist among carriers of the D4Z4 reduced allele (DRA). OBJECTIVE To investigate the clinical expression of FSHD in the genetic subgroup of carriers of a DRA with 7 to 8 repeat units (RUs). DESIGN, SETTING, AND PARTICIPANTS This multicenter cross-sectional study included 422 carriers of DRA with 7 to 8 RUs (187 unrelated probands and 235 relatives) from a consecutive sample of 280 probands and 306 relatives from the Italian National Registry for FSHD collected between 2008 and 2016. Participants were evaluated by the Italian Clinical Network for FSHD, and all clinical and molecular data were collected in the Italian National Registry for FSHD database. Data analysis was conducted from January 2017 to June 2018. MAIN OUTCOMES AND MEASURES The phenotypic classification of probands and relatives was obtained by applying the Comprehensive Clinical Evaluation Form which classifies patients in the 4 following categories: (1) participants presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) participants with muscle weakness limited to scapular girdle or facial muscles (category B, subcategories B1 and B2), (3) asymptomatic or healthy participants (category C, subcategories C1 and C2), and (4) participants with myopathic phenotypes presenting clinical features not consistent with FSHD canonical phenotype (category D, subcategories D1 and D2). RESULTS A total of 187 probands (mean [SD] age at last neurological examination, 53.5 [15.2] years; 103 [55.1%] men) and 235 relatives (mean [SD] age at last neurologic examination, 45.1 [17.0] years; 104 [44.7%] men) with a DRA with 7 to 8 RUs and a molecular diagnosis of FSHD were evaluated. Of 187 probands, 99 (52.9%; 95% CI, 45.7%-60.1%) displayed the classic FSHD phenotype, whereas 86 (47.1%; 95% CI, 39.8%-54.3%) presented incomplete or atypical phenotypes. Of 235 carrier relatives from 106 unrelated families, 124 (52.8%; 95% CI, 46.4%-59.7%) had no motor impairment, whereas a small number (38 [16.2%; 95% CI, 9.8%-23.1%]) displayed the classic FSHD phenotype, and 73 (31.0%; 95% CI, 24.7%-38.0%) presented with incomplete or atypical phenotypes. In 37 of 106 families (34.9%; 95% CI, 25.9%-44.8%), the proband was the only participant presenting with a myopathic phenotype, while only 20 families (18.9%; 95% CI, 11.9%-27.6%) had a member with autosomal dominant FSHD.

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Facioscapulohumeral Muscular Dystrophy: Genetics

Magdinier

Upadhyaya

2018

Encyclopedia of Life Sciences

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Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited muscular dystrophy that presents clinically with progressive weakness of the facial, scapular and humeral muscles, with later involvement of the trunk and lower extremities. FSHD is a unique disease with complex genetic and epigenetic aetiology and the underlying biological mechanisms are still not fully deciphered. FSHD1 is more frequent (95%) and is associated with the contraction of the D4Z4 macrosatellite repeat array located on a permissive 4qA chromosome combined with decreased methylation of cytosines at the 4q35‐linked D4Z4 units. D4Z4 contraction allows epigenetic derepression of the D4Z4 array allowing the expression of the toxic DUX4 transcription factor encoded within the terminal D4Z4 repeat in skeletal muscles. FSHD2 associated with approximately 2–3% of the FSHD patients results from haploinsufficiency of the SMCHD1 gene in individuals carrying a permissive 4qA allele and marked hypomethylation of 4q and 10q D4Z4, which leads to the derepression of DUX4 hence DUX4 appears to be a key player in both types of FSHD. Currently, there is no reliable treatment for this condition, therefore for the successful development of new treatments, an integration of clinical and pathogenetic information is vital. Key Concepts FSHD is the third most common inherited muscular dystrophy characterised by a typical phenotype and involvement of specific groups of muscles. FSHD is characterised by a highly variable penetrance and clinical severity. In most cases, FSHD involves shortening of a repetitive macrosatellite array. The D4Z4 macrosatellite linked to FSHD encodes the DUX4 transcription factor. A small proportion of FSHD patients carry mutation in the SMCHD1 gene. Epigenetic changes in FSHD are closely associated with molecular features. FSHD is a unique disease with complex genetic and epigenetic aetiology and the underlying biological mechanisms are still not fully deciphered. There is no reliable treatment for the disease.

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Large-Scale Population Analysis Challenges the Current Criteria for the Molecular Diagnosis of Fascioscapulohumeral Muscular Dystrophy

Cited by 107 publications

References 43 publications

Facioscapulohumeral Muscular Dystrophy: From Clinical Data to Molecular Genetics and Return

Facioscapulohumeral Muscular Dystrophy: From Clinical Data to Molecular Genetics and Return

Phenotypic Variability Among Patients With D4Z4 Reduced Allele Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral Muscular Dystrophy: Genetics

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