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

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 rel...

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Autores principales: Nikolic, Ana, Jones, Takako I, Govi, Monica, Mele, Fabiano, Maranda, Louise, Sera, Francesco, Ricci, Giulia, Ruggiero, Lucia, Vercelli, Liliana, Portaro, Simona, Villa, Luisa, Fiorillo, Chiara, Maggi, Lorenzo, Santoro, Lucio, Antonini, Giovanni, Filosto, Massimiliano, Moggio, Maurizio, Angelini, Corrado, Pegoraro, Elena, Berardinelli, Angela, Maioli, Maria Antonetta, D’Angelo, Grazia, Di Muzio, Antonino, Siciliano, Gabriele, Tomelleri, Giuliano, D’Esposito, Maurizio, Della Ragione, Floriana, Brancaccio, Arianna, Piras, Rachele, Rodolico, Carmelo, Mongini, Tiziana, Magdinier, Frederique, Salsi, Valentina, Jones, Peter L., Tupler, Rossella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178248/
https://www.ncbi.nlm.nih.gov/pubmed/32290091
http://dx.doi.org/10.3390/ijms21072635
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author Nikolic, Ana
Jones, Takako I
Govi, Monica
Mele, Fabiano
Maranda, Louise
Sera, Francesco
Ricci, Giulia
Ruggiero, Lucia
Vercelli, Liliana
Portaro, Simona
Villa, Luisa
Fiorillo, Chiara
Maggi, Lorenzo
Santoro, Lucio
Antonini, Giovanni
Filosto, Massimiliano
Moggio, Maurizio
Angelini, Corrado
Pegoraro, Elena
Berardinelli, Angela
Maioli, Maria Antonetta
D’Angelo, Grazia
Di Muzio, Antonino
Siciliano, Gabriele
Tomelleri, Giuliano
D’Esposito, Maurizio
Della Ragione, Floriana
Brancaccio, Arianna
Piras, Rachele
Rodolico, Carmelo
Mongini, Tiziana
Magdinier, Frederique
Salsi, Valentina
Jones, Peter L.
Tupler, Rossella
author_facet Nikolic, Ana
Jones, Takako I
Govi, Monica
Mele, Fabiano
Maranda, Louise
Sera, Francesco
Ricci, Giulia
Ruggiero, Lucia
Vercelli, Liliana
Portaro, Simona
Villa, Luisa
Fiorillo, Chiara
Maggi, Lorenzo
Santoro, Lucio
Antonini, Giovanni
Filosto, Massimiliano
Moggio, Maurizio
Angelini, Corrado
Pegoraro, Elena
Berardinelli, Angela
Maioli, Maria Antonetta
D’Angelo, Grazia
Di Muzio, Antonino
Siciliano, Gabriele
Tomelleri, Giuliano
D’Esposito, Maurizio
Della Ragione, Floriana
Brancaccio, Arianna
Piras, Rachele
Rodolico, Carmelo
Mongini, Tiziana
Magdinier, Frederique
Salsi, Valentina
Jones, Peter L.
Tupler, Rossella
author_sort Nikolic, Ana
collection PubMed
description 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.
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spelling pubmed-71782482020-04-28 Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies Nikolic, Ana Jones, Takako I Govi, Monica Mele, Fabiano Maranda, Louise Sera, Francesco Ricci, Giulia Ruggiero, Lucia Vercelli, Liliana Portaro, Simona Villa, Luisa Fiorillo, Chiara Maggi, Lorenzo Santoro, Lucio Antonini, Giovanni Filosto, Massimiliano Moggio, Maurizio Angelini, Corrado Pegoraro, Elena Berardinelli, Angela Maioli, Maria Antonetta D’Angelo, Grazia Di Muzio, Antonino Siciliano, Gabriele Tomelleri, Giuliano D’Esposito, Maurizio Della Ragione, Floriana Brancaccio, Arianna Piras, Rachele Rodolico, Carmelo Mongini, Tiziana Magdinier, Frederique Salsi, Valentina Jones, Peter L. Tupler, Rossella Int J Mol Sci Article 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. MDPI 2020-04-10 /pmc/articles/PMC7178248/ /pubmed/32290091 http://dx.doi.org/10.3390/ijms21072635 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nikolic, Ana
Jones, Takako I
Govi, Monica
Mele, Fabiano
Maranda, Louise
Sera, Francesco
Ricci, Giulia
Ruggiero, Lucia
Vercelli, Liliana
Portaro, Simona
Villa, Luisa
Fiorillo, Chiara
Maggi, Lorenzo
Santoro, Lucio
Antonini, Giovanni
Filosto, Massimiliano
Moggio, Maurizio
Angelini, Corrado
Pegoraro, Elena
Berardinelli, Angela
Maioli, Maria Antonetta
D’Angelo, Grazia
Di Muzio, Antonino
Siciliano, Gabriele
Tomelleri, Giuliano
D’Esposito, Maurizio
Della Ragione, Floriana
Brancaccio, Arianna
Piras, Rachele
Rodolico, Carmelo
Mongini, Tiziana
Magdinier, Frederique
Salsi, Valentina
Jones, Peter L.
Tupler, Rossella
Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies
title Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies
title_full Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies
title_fullStr Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies
title_full_unstemmed Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies
title_short Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies
title_sort interpretation of the epigenetic signature of facioscapulohumeral muscular dystrophy in light of genotype-phenotype studies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178248/
https://www.ncbi.nlm.nih.gov/pubmed/32290091
http://dx.doi.org/10.3390/ijms21072635
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