Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies - Archive ouverte HAL Access content directly
Journal Articles International Journal of Molecular Sciences Year : 2020

Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies

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Ana Nikolic
  • Function : Author
Takako Jones
  • Function : Author
Monica Govi
  • Function : Author
Fabiano Mele
  • Function : Author
Louise Maranda
  • Function : Author
Francesco Sera
  • Function : Author
Giulia Ricci
  • Function : Author
Lucia Ruggiero
  • Function : Author
Liliana Vercelli
  • Function : Author
Simona Portaro
  • Function : Author
Luisa Villa
  • Function : Author
Chiara Fiorillo
  • Function : Author
Lorenzo Maggi
  • Function : Author
Lucio Santoro
  • Function : Author
Giovanni Antonini
  • Function : Author
Massimiliano Filosto
Maurizio Moggio
  • Function : Author
Corrado Angelini
  • Function : Author
Elena Pegoraro
  • Function : Author
Angela Berardinelli
  • Function : Author
Maria Antonetta Maioli
  • Function : Author
Grazia D’angelo
  • Function : Author
Antonino Di Muzio
  • Function : Author
Gabriele Siciliano
  • Function : Author
Giuliano Tomelleri
  • Function : Author
Maurizio D’esposito
  • Function : Author
Floriana Della Ragione
  • Function : Author
Arianna Brancaccio
  • Function : Author
Rachele Piras
  • Function : Author
Carmelo Rodolico
  • Function : Author
Tiziana Mongini
  • Function : Author
Valentina Salsi
  • Function : Author
Peter Jones
Rossella Tupler
  • Function : Author

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by incomplete penetrance and intra-familial clinical variability. The disease has been associated with the genetic and epigenetic features of the D4Z4 repetitive elements at 4q35. Recently, D4Z4 hypomethylation has been proposed as a reliable marker in the FSHD diagnosis. We exploited the Italian Registry for FSHD, in which FSHD families are classified using the Clinical Comprehensive Evaluation Form (CCEF). A total of 122 index cases showing a classical FSHD phenotype (CCEF, category A) and 110 relatives were selected to test with the receiver operating characteristic (ROC) curve, the diagnostic and predictive value of D4Z4 methylation. Moreover, we performed DNA methylation analysis in selected large families with reduced penetrance characterized by the co-presence of subjects carriers of one D4Z4 reduced allele with no signs of disease or presenting the classic FSHD clinical phenotype. We observed a wide variability in the D4Z4 methylation levels among index cases revealing no association with clinical manifestation or disease severity. By extending the analysis to family members, we revealed the low predictive value of D4Z4 methylation in detecting the affected condition. In view of the variability in D4Z4 methylation profiles observed in our large cohort, we conclude that D4Z4 methylation does not mirror the clinical expression of FSHD. We recommend that measurement of this epigenetic mark must be interpreted with caution in clinical practice.

Dates and versions

hal-03142878 , version 1 (16-02-2021)

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Ana Nikolic, Takako Jones, Monica Govi, Fabiano Mele, Louise Maranda, et al.. Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies. International Journal of Molecular Sciences, 2020, 21 (7), pp.2635. ⟨10.3390/ijms21072635⟩. ⟨hal-03142878⟩

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