Abstract
| Original language | English |
|---|---|
| Article number | 2635 |
| Number of pages | 18 |
| Journal | Int. J. Mol. Sci. |
| Volume | 21 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 2020 |
Keywords
- D4Z4 reduced allele
- DNA methylation
- FSHD
- Genotype-phenotype correlation
- Molecular diagnosis
- area under the curve
- Article
- clinical evaluation
- clinical feature
- clinical practice
- CpG island
- disease severity
- DNA determination
- DNA sequence
- epigenetics
- facioscapulohumeral muscular dystrophy
- gene expression
- genotype
- human
- muscular dystrophy
- phenotype
- predictive value
- protein expression
- receiver operating characteristic
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Interpretation of the epigenetic signature of facioscapulohumeral muscular dystrophy in light of genotype-phenotype studies : International Journal of Molecular Sciences. / Nikolic, A.; Jones, T.I.; Govi, M. et al.
In: Int. J. Mol. Sci., Vol. 21, No. 7, 2635, 2020.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Interpretation of the epigenetic signature of facioscapulohumeral muscular dystrophy in light of genotype-phenotype studies
T2 - International Journal of Molecular Sciences
AU - Nikolic, A.
AU - Jones, T.I.
AU - Govi, M.
AU - Mele, F.
AU - Maranda, L.
AU - Sera, F.
AU - Ricci, G.
AU - Ruggiero, L.
AU - Vercelli, L.
AU - Portaro, S.
AU - Villa, L.
AU - Fiorillo, C.
AU - Maggi, L.
AU - Santoro, L.
AU - Antonini, G.
AU - Filosto, M.
AU - Moggio, M.
AU - Angelini, C.
AU - Pegoraro, E.
AU - Berardinelli, A.
AU - Maioli, M.A.
AU - D’Angelo, G.
AU - Di Muzio, A.
AU - Siciliano, G.
AU - Tomelleri, G.
AU - D’Esposito, M.
AU - Ragione, F.D.
AU - Brancaccio, A.
AU - Piras, R.
AU - Rodolico, C.
AU - Mongini, T.
AU - Magdinier, F.
AU - Salsi, V.
AU - Jones, P.L.
AU - Tupler, R.
N1 - Export Date: 24 July 2020 Correspondence Address: Tupler, R.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio EmiliaItaly; email: rossella.tupler@unimore.it Funding details: AFM Telethon16593, GUP13012 Funding details: 01AR062587 Funding text 1: Funding: This research was funded by Telethon Italy GUP13012, AFM Telethon16593, Regione Emilia Romagna RARER, and grant #R01AR062587 from the NIAMS/NIH to P.L.J. References: Padberg, G.W.A.M., (1982) Facioscapulohumeral Disease, , Leiden University: Leiden, The Netherlands; Mostacciuolo, M.L., Pastorello, E., Vazza, G., Miorin, M., Angelini, C., Tomelleri, G., Galluzzi, G., Trevisan, C.P., Facioscapulohumeral muscular dystrophy: Epidemiological and molecular study in a north-east Italian population sample (2009) Clin. Genet., 75, pp. 550-555; Goto, K., Nishino, I., Hayashi, Y.K., Very low penetrance in 85 Japanese families with facioscapulohumeral muscular dystrophy 1A (2004) J. Med. Genet., 41, p. e12; Nakagawa, M., Matsuzaki, T., Higuchi, I., Fukunaga, H., Inui, T., Nagamitsu, S., Yamada, H., Osame, M., Facioscapulohumeral Muscular Dystrophy: Clinical Diversity and Genetic Abnormalities in Japanese Patients (1997) Intern. Med., 36, pp. 333-339; Jones, T.I., Chen, J.C.J., Rahimov, F., Homma, S., Arashiro, P., Beermann, M.L., King, O.D., Emerson, C.P., Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: Evidence for disease modifiers and a quantitative model of pathogenesis (2012) Hum. Mol. Genet., 21, pp. 4419-4430; Wijmenga, C., Hewitt, J.E., Sandkuijl, L.A., Clark, L.N., Wright, T.J., Dauwerse, H.G., Gruter, A.-M., Williamson, R., Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy (1992) Nat. Genet., 2, pp. 26-30; Deutekom, J.C.T.V., Wljmenga, C., Tlenhoven, E.A.E.V., Gruter, A.-M., Hewitt, J.E., Padberg, G.W., van Ommen, G.-J.B., Fronts, R.R., FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit (1993) Hum. Mol. Genet., 2, pp. 2037-2042; Deidda, G., Cacurri, S., Piazzo, N., Felicetti, L., Direct detection of 4q35 rearrangements implicated in facioscapulohumeral muscular dystrophy (FSHD) (1996) J. Med. Genet., 33, pp. 361-365; Lunt, P., 44th ENMC InternationalWorkshop: Facioscapulohumeral Muscular Dystrophy: Molecular Studies:19-21 July 1996, Naarden, The Netherlands (1998) Neuromuscul. Disord., 8, pp. 126-130; Scionti, I., Greco, F., Ricci, G., Govi, M., Arashiro, P., Vercelli, L., Berardinelli, A., Cao, M., Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy (2012) Am. J. Hum. 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Neurol., 250, pp. 932-937; Wohlgemuth, M., Lemmers, R.J., van der Kooi, E.L., van der Wielen, M.J., van Overveld, P.G., Dauwerse, H., Bakker, E., van der Maarel, S.M., Possible phenotypic dosage effect in patients compound heterozygous for FSHD-sized 4q35 alleles (2003) Neurology, 61, pp. 909-913; Larsen, M., Rost, S., El Hajj, N., Ferbert, A., Deschauer, M., Walter, M.C., Schoser, B., Müller, C.R., Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1 (2015) Eur. J. Hum. Genet., 23, pp. 808-816; Ricci, G., Scionti, I., Sera, F., Govi, M., D’Amico, R., Frambolli, I., Mele, F., Ruggiero, L., Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy (2013) Brain, 136, pp. 3408-3417; Ricci, G., Zatz, M., Tupler, R., Facioscapulohumeral Muscular Dystrophy: More Complex than it Appears (2014) Curr. Mol. Med., 14, pp. 1052-1068; Salort-Campana, E., Nguyen, K., Bernard, R., Jouve, E., Solé, G., Nadaj-Pakleza, A., Niederhauser, J., Bouhour, F., Low penetrance in facioscapulohumeral muscular dystrophy type 1 with large pathological D4Z4 alleles: A cross-sectional multicenter study (2015) Orphanet J. Rare Dis., 10, p. 2; Ricci, G., Ruggiero, L., Vercelli, L., Sera, F., Nikolic, A., Govi, M., Mele, F., Antonini, G., A novel clinical tool to classify facioscapulohumeral muscular dystrophy phenotypes (2016) J. Neurol., 263, pp. 1204-1214; van Overveld, P.G.M., Lemmers, R.J.F.L., Sandkuijl, L.A., Enthoven, L., Winokur, S.T., Bakels, F., Padberg, G.W., van der Maarel, S.M., Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy (2003) Nat. Genet., 35, pp. 315-317; de Greef, J.C., Lemmers, R.J.L.F., van Engelen, B.G.M., Sacconi, S., Venance, S.L., Frants, R.R., Tawil, R., van der Maarel, S.M., Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD (2009) Hum. Mutat., 30, pp. 1449-1459; Lemmers, R.J.L.F., Tawil, R., Petek, L.M., Balog, J., Block, G.J., Santen, G.W.E., Amell, A.M., Straasheijm, K.R., Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2 (2012) Nat. Genet., 44, pp. 1370-1374; Balog, J., Thijssen, P.E., Shadle, S., Straasheijm, K.R., van der Vliet, P.J., Krom, Y.D., van den Boogaard, M.L., Tawil, R., Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4 (2015) Epigenetics, 10, pp. 1133-1142; Calandra, P., Cascino, I., Lemmers, R.J.L.F.L.F., Galluzzi, G., Teveroni, E., Monforte, M., Tasca, G., van der Maarel, S.M., Allele-specific DNA hypomethylation characterises FSHD1 and FSHD2 (2016) J. Med. Genet., 53, pp. 348-355; Hartweck, L.M., Anderson, L.J., Lemmers, R.J., Dandapat, A., Toso, E.A., Dalton, J.C., Tawil, R., Kyba, M., A focal domain of extreme demethylation within D4Z4 in FSHD2 (2013) Neurology, 80, pp. 392-399; Gaillard, M.-C., Roche, S., Dion, C., Tasmadjian, A., Bouget, G., Salort-Campana, E., Vovan, C., Morere, J., Differential DNA methylation of the D4Z4 repeat in patients with FSHD and asymptomatic carriers (2014) Neurology, 83, pp. 733-742; Jones, T.I., Yan, C., Sapp, P.C., McKenna-Yasek, D., Kang, P.B., Quinn, C., Salameh, J.S., Jones, P.L., Identifying diagnostic DNA methylation profiles for facioscapulohumeral muscular dystrophy in blood and saliva using bisulfite sequencing (2014) Clin. Epigenetics, 6, p. 23; Lemmers, R.J.L.F., Goeman, J.J., van der Vliet, P.J., van Nieuwenhuizen, M.P., Balog, J., Vos-Versteeg, M., Camano, P., Rogers, M.T., A standardized clinical evaluation of patients affected by facioscapulohumeral muscular dystrophy: The FSHD clinical score (2010) Muscle Nerve, 42, pp. 213-217; Jones, T.I., King, O.D., Himeda, C.L., Homma, S., Chen, J.C.J.J., Beermann, M.L., Yan, C., Wagner, K.R., Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2 (2015) Hum. Mol. Genet., 24, pp. 659-669; Jones, T.I., Himeda, C.L., Perez, D.P., Jones, P.L., Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy (2015) Clin. Epigenetics, 7, p. 37; Jones, T.I., Himeda, C.L., Perez, D.P., Jones, P.L., Large family cohorts of lymphoblastoid cells provide a new cellular model for investigating facioscapulohumeral muscular dystrophy (2017) Neuromuscul. Disord., 27, pp. 221-238; Van Overveld, P.G.M., Enthoven, L., Ricci, E., Rossi, M., Felicetti, L., Jeanpierre, M., Winokur, S.T., van der Maarel, S.M., Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy (2016) Am. J. Hum. Genet., 98, pp. 1020-1029; de Greef, J.C., Wohlgemuth, M., Chan, O.A., Hansson, K.B., Smeets, D., Frants, R.R., Weemaes, C.M., van der Maarel, S.M., Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy (2005) Ann. 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PY - 2020
Y1 - 2020
N2 - 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, MDPI AG. All rights reserved.
AB - 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, MDPI AG. All rights reserved.
KW - D4Z4 reduced allele
KW - DNA methylation
KW - FSHD
KW - Genotype-phenotype correlation
KW - Molecular diagnosis
KW - area under the curve
KW - Article
KW - clinical evaluation
KW - clinical feature
KW - clinical practice
KW - CpG island
KW - disease severity
KW - DNA determination
KW - DNA sequence
KW - epigenetics
KW - facioscapulohumeral muscular dystrophy
KW - gene expression
KW - genotype
KW - human
KW - muscular dystrophy
KW - phenotype
KW - predictive value
KW - protein expression
KW - receiver operating characteristic
U2 - 10.3390/ijms21072635
DO - 10.3390/ijms21072635
M3 - Article
SN - 1661-6596
VL - 21
JO - Int. J. Mol. Sci.
JF - Int. J. Mol. Sci.
IS - 7
M1 - 2635
ER -