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.

Interpretation of the epigenetic signature of facioscapulohumeral muscular dystrophy in light of genotype-phenotype studies / Nikolic, A.; Jones, T. I.; Govi, M.; Mele, F.; Maranda, L.; Sera, F.; Ricci, G.; Ruggiero, L.; Vercelli, L.; Portaro, S.; Villa, L.; Fiorillo, C.; Maggi, L.; Santoro, L.; Antonini, G.; Filosto, M.; Moggio, M.; Angelini, C.; Pegoraro, E.; Berardinelli, A.; Maioli, M. A.; D'Angelo, G.; Di Muzio, A.; Siciliano, G.; Tomelleri, G.; D'Esposito, M.; Ragione, F. D.; Brancaccio, A.; Piras, R.; Rodolico, C.; Mongini, T.; Magdinier, F.; Salsi, V.; Jones, P. L.; Tupler, R.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 21:7(2020), pp. 2635-2654. [10.3390/ijms21072635]

Interpretation of the epigenetic signature of facioscapulohumeral muscular dystrophy in light of genotype-phenotype studies

Salsi V.;Tupler R.
2020

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.
2020
21
7
2635
2654
Interpretation of the epigenetic signature of facioscapulohumeral muscular dystrophy in light of genotype-phenotype studies / Nikolic, A.; Jones, T. I.; Govi, M.; Mele, F.; Maranda, L.; Sera, F.; Ricci, G.; Ruggiero, L.; Vercelli, L.; Portaro, S.; Villa, L.; Fiorillo, C.; Maggi, L.; Santoro, L.; Antonini, G.; Filosto, M.; Moggio, M.; Angelini, C.; Pegoraro, E.; Berardinelli, A.; Maioli, M. A.; D'Angelo, G.; Di Muzio, A.; Siciliano, G.; Tomelleri, G.; D'Esposito, M.; Ragione, F. D.; Brancaccio, A.; Piras, R.; Rodolico, C.; Mongini, T.; Magdinier, F.; Salsi, V.; Jones, P. L.; Tupler, R.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 21:7(2020), pp. 2635-2654. [10.3390/ijms21072635]
Nikolic, A.; Jones, T. I.; Govi, M.; Mele, F.; Maranda, L.; Sera, F.; Ricci, G.; Ruggiero, L.; Vercelli, L.; Portaro, S.; Villa, L.; Fiorillo, C.; Mag...espandi
File in questo prodotto:
File Dimensione Formato  
ijms-21-02635.pdf

Open access

Tipologia: Versione pubblicata dall'editore
Dimensione 5.01 MB
Formato Adobe PDF
5.01 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1202113
Citazioni
  • ???jsp.display-item.citation.pmc??? 14
  • Scopus 14
  • ???jsp.display-item.citation.isi??? 13
social impact