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

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Department of Science of Life, Institute of Biology, University of Modena and Reggio Emilia, 41125 Modena, Italy
2
Department of Pharmacology, School of Medicine, University of Nevada, Reno, NV 89557, USA
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Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy
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Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Department of Public Health, Environments and Society, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
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Department of Clinical and Experimental Medicine, Neurological Clinic, 56126 Pisa, Italy
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Department of Neurosciences and Reproductive and Odontostomatologic Sciences, University Federico II, 80137 Naples, Italy
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Department of Neurosciences “Rita Levi Montalcini”, University of Turin, 10124 Turin, Italy
9
Department of Neuroscience, Mental Health and Sensory Organs, S. Andrea Hospital, University of Rome “Sapienza”, 00185 Rome, Italy
10
Department of Neuroscience, Foundation IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy
11
Pediatric Neurology and Neuromuscular Disorders Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16126 Genoa, Italy
12
IRCCS Foundation, C. Besta Neurological Institute, 20133 Milan, Italy
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Neurology Clinic, ‘‘Spedali Civili’’. Hospital, 25123 Brescia, Italy
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Ospedale S.Camillo IRCCS, Lido di Venezia, 20126 Venezia, Italy
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Department of Neurosciences, University of Padua, 35128 Padua, Italy
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Neurology and Psychiatry, IRCCS Institute ‘C.Mondino’ Foundation, 27100 Pavia, Italy
17
ASL8, Centro Sclerosi Multipla, 09126 Cagliari, Italy
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Department of Neurorehabilitation, IRCCS Institute Eugenio Medea, 23842 Bosisio Parini, Italy
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Center for Neuromuscular Disease, CeSI, University ‘‘G. D’Annunzio’’, 66100 Chieti, Italy
20
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
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Institute of Genetics and Biophysics, A. Buzzati Traverso, IGB, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy
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Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
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Aix Marseille Univ, INSERM, MMG, U 1251, 13005 Marseille, France
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Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, 41125 Modena, Italy
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Department of Molecular Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
26
Li Weibo Institute for Rare Diseases Research at the University of Massachusetts Medical School, Worcester, MA 01605, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(7), 2635; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072635
Received: 2 March 2020 / Revised: 31 March 2020 / Accepted: 7 April 2020 / Published: 10 April 2020
(This article belongs to the Special Issue Epigenetic Alterations in Neuromuscular Disorders)
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. View Full-Text
Keywords: FSHD; D4Z4 reduced allele; DNA methylation; genotype–phenotype correlation; molecular diagnosis FSHD; D4Z4 reduced allele; DNA methylation; genotype–phenotype correlation; molecular diagnosis
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MDPI and ACS Style

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.; Della Ragione, F.; Brancaccio, A.; Piras, R.; Rodolico, C.; Mongini, T.; Magdinier, F.; Salsi, V.; Jones, P.L.; Tupler, R. Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies. Int. J. Mol. Sci. 2020, 21, 2635. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072635

AMA Style

Nikolic A, Jones TI, 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 MA, D’Angelo G, Di Muzio A, Siciliano G, Tomelleri G, D’Esposito M, Della Ragione F, Brancaccio A, Piras R, Rodolico C, Mongini T, Magdinier F, Salsi V, Jones PL, Tupler R. Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies. International Journal of Molecular Sciences. 2020; 21(7):2635. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072635

Chicago/Turabian Style

Nikolic, Ana, Takako I. Jones, Monica Govi, Fabiano Mele, Louise Maranda, Francesco Sera, Giulia Ricci, Lucia Ruggiero, Liliana Vercelli, Simona Portaro, Luisa Villa, Chiara Fiorillo, Lorenzo Maggi, Lucio Santoro, Giovanni Antonini, Massimiliano Filosto, Maurizio Moggio, Corrado Angelini, Elena Pegoraro, Angela Berardinelli, Maria A. Maioli, Grazia D’Angelo, Antonino Di Muzio, Gabriele Siciliano, Giuliano Tomelleri, Maurizio D’Esposito, Floriana Della Ragione, Arianna Brancaccio, Rachele Piras, Carmelo Rodolico, Tiziana Mongini, Frederique Magdinier, Valentina Salsi, Peter L. Jones, and Rossella Tupler. 2020. "Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies" International Journal of Molecular Sciences 21, no. 7: 2635. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072635

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