The Genetics and Epigenetics of Facioscapulohumeral Muscular Dystrophy

Literature Cited

1. 1.

   Alexandrov PN, Zhao Y, Jaber V, Cong L, Lukiw WJ 2017. Deficits in the proline-rich synapse-associated Shank3 protein in multiple neuropsychiatric disorders. Front. Neurol. 8:670
   [Google Scholar]
2. 2.

   An S, Song JJ. 2011. The coded functions of noncoding RNAs for gene regulation. Mol. Cells 31:491–96
   [Google Scholar]
3. 3.

   Ansseau E, Vanderplanck C, Wauters A, Harper SQ, Coppee F, Belayew A 2017. Antisense oligonucleotides used to target the DUX4 mRNA as therapeutic approaches in faciosscapulohumeral muscular dystrophy (FSHD). Genes 8:93
   [Google Scholar]
4. 4.

   Arashiro P, Eisenberg I, Kho AT, Cerqueira AM, Canovas M et al. 2009. Transcriptional regulation differs in affected facioscapulohumeral muscular dystrophy patients compared to asymptomatic related carriers. PNAS 106:6220–25
   [Google Scholar]
5. 5.

   Ashe A, Morgan DK, Whitelaw NC, Bruxner TJ, Vickaryous NK et al. 2008. A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development. Genome Biol 9:R182
   [Google Scholar]
6. 6.

   Ashraf W, Ibrahim A, Alhosin M, Zaayter L, Ouararhni K et al. 2017. The epigenetic integrator UHRF1: on the road to become a universal biomarker for cancer. Oncotarget 8:51946–62
   [Google Scholar]
7. 7.

   Bakker E, Wijmenga C, Vossen RH, Padberg GW, Hewitt J et al. 1995. The FSHD-linked locus D4F104S1 (p13E-11) on 4q35 has a homologue on 10qter. Muscle Nerve 2:S39–44
   [Google Scholar]
8. 8.

   Balog J, Thijssen PE, de Greef JC, Shah B, van Engelen BG et al. 2012. Correlation analysis of clinical parameters with epigenetic modifications in the DUX4 promoter in FSHD. Epigenetics 7:579–84
   [Google Scholar]
9. 9.

   Bateson W. 1908. The Methods and Scope of Genetics Cambridge, UK: Cambridge Univ. Press
10. 10.

    Becker PB, Horz W. 2002. ATP-dependent nucleosome remodeling. Annu. Rev. Biochem. 71:247–73
    [Google Scholar]
11. 11.

    Berdasco M, Esteller M. 2013. Genetic syndromes caused by mutations in epigenetic genes. Hum. Genet. 132:359–83
    [Google Scholar]
12. 12.

    Blewitt ME, Gendrel AV, Pang Z, Sparrow DB, Whitelaw N et al. 2008. SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation. Nat. Genet. 40:663–69
    [Google Scholar]
13. 13.

    Blewitt ME, Vickaryous NK, Hemley SJ, Ashe A, Bruxner TJ et al. 2005. An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse. PNAS 102:7629–34
    [Google Scholar]
14. 14.

    Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR et al. 1998. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248–57
    [Google Scholar]
15. 15.

    Bosma JF, Henkin RI, Christiansen RL, Herdt JR 1981. Hypoplasia of the nose and eyes, hyposmia, hypogeusia, and hypogonadotrophic hypogonadism in two males. J. Craniofac. Genet. Dev. Biol. 1:153–84
    [Google Scholar]
16. 16.

    Bosnakovski D, Chan SSK, Recht OO, Hartweck LM, Gustafson CJ et al. 2017. Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model. Nat. Commun. 8:550
    [Google Scholar]
17. 17.

    Bosnakovski D, Toso EA, Hartweck LM, Magli A, Lee HA et al. 2017. The DUX4 homeodomains mediate inhibition of myogenesis and are functionally exchangeable with the Pax7 homeodomain. J. Cell Sci. 130:3685–97
    [Google Scholar]
18. 18.

    Bosnakovski D, Xu Z, Gang EJ, Galindo CL, Liu M et al. 2008. An isogenetic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies. EMBO J 27:2766–79
    [Google Scholar]
19. 19.

    Brasseur B, Martin CM, Cayci Z, Burmeister L, Schimmenti LA 2016. Bosma arhinia microphthalmia syndrome: clinical report and review of the literature. Am. J. Med. Genet. A 170A:1302–7
    [Google Scholar]
20. 20.

    Brideau NJ, Coker H, Gendrel AV, Siebert CA, Bezstarosti K et al. 2015. Independent mechanisms target SMCHD1 to trimethylated histone H3 lysine 9-modified chromatin and the inactive X chromosome. Mol. Cell. Biol. 35:4053–68
    [Google Scholar]
21. 21.

    Brook MH. 1977. A Clinician's View of Neuromuscular Diseases Baltimore, MD: Williams & Wilkins
22. 22.

    Brouwer OF, Padberg GW, Wijmenga C, Frants RR 1994. Facioscapulohumeral muscular dystrophy in early childhood. Arch. Neurol. 51:387–94
    [Google Scholar]
23. 23.

    Cabianca DS, Casa V, Bodega B, Xynos A, Ginelli E et al. 2012. A long ncRNA links copy number variation to a Polycomb/Trithorax epigenetic switch in FSHD muscular dystrophy. Cell 149:819–31
    [Google Scholar]
24. 24.

    Calandra P, Cascino I, Lemmers RJ, Galluzzi G, Teveroni E et al. 2016. Allele-specific DNA hypomethylation characterises FSHD1 and FSHD2. J. Med. Genet. 53:348–55
    [Google Scholar]
25. 25.

    Campbell AE, Belleville A, Resnick R, Shadle SC, Tapscott SJ 2018. Facioscapulohumeral dystrophy: activating an early embryonic transcriptional program in human skeletal muscle. Hum. Mol. Genet. 27:R153–62
    [Google Scholar]
26. 26.

    Campbell AE, Oliva J, Yates MP, Zhong JW, Shadle SC et al. 2017. BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells. Skelet. Muscle 7:16
    [Google Scholar]
27. 27.

    Chen K, Hu J, Moore DL, Liu R, Kessans SA et al. 2015. Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation. PNAS 112:E3535–44
    [Google Scholar]
28. 28.

    Chen TH, Lai YH, Lee PL, Hsu JH, Goto K et al. 2013. Infantile facioscapulohumeral muscular dystrophy revisited: expansion of clinical phenotypes in patients with a very short EcoRI fragment. Neuromuscul. Disord. 23:298–305
    [Google Scholar]
29. 29.

    Choi SH, Bosnakovski D, Strasser JM, Toso EA, Walters MA, Kyba M 2016. Transcriptional inhibitors identified in a 160,000-compound small-molecule DUX4 viability screen. J. Biomol. Screen. 21:680–88
    [Google Scholar]
30. 30.

    Clapp J, Mitchell LM, Bolland DJ, Fantes J, Corcoran AE et al. 2007. Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy. Am. J. Hum. Genet. 81:264–79
    [Google Scholar]
31. 31.

    Cohen CJ, Lock WM, Mager DL 2009. Endogenous retroviral LTRs as promoters for human genes: a critical assessment. Gene 448:105–14
    [Google Scholar]
32. 32.

    Cowley M, Oakey RJ. 2013. Transposable elements re-wire and fine-tune the transcriptome. PLOS Genet 9:e1003234
    [Google Scholar]
33. 33.

    Cruz JM Jr, Hupper N, Wilson LS, Concannon JB, Wang Y et al. 2018. Protein kinase A activation inhibits DUX4 gene expression in myotubes from patients with facioscapulohumeral muscular dystrophy. J. Biol. Chem. 293:11837–49
    [Google Scholar]
34. 34.

    Daxinger L, Harten SK, Oey H, Epp T, Isbel L et al. 2013. An ENU mutagenesis screen identifies novel and known genes involved in epigenetic processes in the mouse. Genome Biol 14:R96
    [Google Scholar]
35. 35.

    Daxinger L, Oey H, Apedaile A, Sutton J, Ashe A, Whitelaw E 2012. A forward genetic screen identifies eukaryotic translation initiation factor 3, subunit H (eIF3h), as an enhancer of variegation in the mouse. G3 2:1393–96
    [Google Scholar]
36. 36.

    de Greef JC, Lemmers RJ, Camano P, Day JW, Sacconi S et al. 2010. Clinical features of facioscapulohumeral muscular dystrophy 2. Neurology 75:1548–54
    [Google Scholar]
37. 37.

    de Greef JC, Lemmers RJ, van Engelen BG, Sacconi S, Venance SL et al. 2009. Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD. Hum. Mutat. 30:1449–59
    [Google Scholar]
38. 38.

    De Iaco A, Planet E, Coluccio A, Verp S, Duc J, Trono D 2017. DUX-family transcription factors regulate zygotic genome activation in placental mammals. Nat. Genet. 49:941–45
    [Google Scholar]
39. 39.

    Deenen JC, Arnts H, van der Maarel SM, Padberg GW, Verschuuren JJ et al. 2014. Population-based incidence and prevalence of facioscapulohumeral dystrophy. Neurology 83:1056–59
    [Google Scholar]
40. 40.

    Deidda G, Cacurri S, Grisanti P, Vigneti E, Piazzo N, Felicetti L 1995. Physical mapping evidence for a duplicated region on chromosome 10qter showing high homology with the facioscapulohumeral muscular dystrophy locus on chromosome 4qter. Eur. J. Hum. Genet. 3:155–67
    [Google Scholar]
41. 41.

    Dixit M, Ansseau E, Tassin A, Winokur S, Shi R et al. 2007. DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1. . PNAS 104:18157–62
    [Google Scholar]
42. 42.

    Dmitriev P, Bou Saada Y, Dib C, Ansseau E, Barat A et al. 2016. DUX4-induced constitutive DNA damage and oxidative stress contribute to aberrant differentiation of myoblasts from FSHD patients. Free Radic. Biol. Med. 99:244–58
    [Google Scholar]
43. 43.

    Feng Q, Snider L, Jagannathan S, Tawil R, van der Maarel SM et al. 2015. A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy. eLife 4:e04996
    [Google Scholar]
44. 44.

    Ferreboeuf M, Mariot V, Bessieres B, Vasiljevic A, Attie-Bitach T et al. 2014. DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles. Hum. Mol. Genet. 23:171–81
    [Google Scholar]
45. 45.

    Feschotte C. 2008. Transposable elements and the evolution of regulatory networks. Nat. Rev. Genet. 9:397–405
    [Google Scholar]
46. 46.

    Gabriels J, Beckers MC, Ding H, De Vriese A, Plaisance S et al. 1999. Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. Gene 236:25–32
    [Google Scholar]
47. 47.

    Garcia-Perez JL, Widmann TJ, Adams IR 2016. The impact of transposable elements on mammalian development. Development 143:4101–14
    [Google Scholar]
48. 48.

    Gendrel AV, Apedaile A, Coker H, Termanis A, Zvetkova I et al. 2012. Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome. Dev. Cell 23:265–79
    [Google Scholar]
49. 49.

    Gendrel AV, Tang YA, Suzuki M, Godwin J, Nesterova TB et al. 2013. Epigenetic functions of Smchd1 repress gene clusters on the inactive X chromosome and on autosomes. Mol. Cell. Biol. 33:3150–65
    [Google Scholar]
50. 50.

    Geng LN, Yao Z, Snider L, Fong AP, Cech JN et al. 2012. DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev. Cell 22:38–51
    [Google Scholar]
51. 51.

    Gifford WD, Pfaff SL, Macfarlan TS 2013. Transposable elements as genetic regulatory substrates in early development. Trends Cell Biol 23:218–26
    [Google Scholar]
52. 52.

    Goodwin LR, Picketts DJ. 2018. The role of ISWI chromatin remodeling complexes in brain development and neurodevelopmental disorders. Mol. Cell. Neurosci. 87:55–64
    [Google Scholar]
53. 53.

    Gordon CT, Xue S, Yigit G, Filali H, Chen K et al. 2017. De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development. Nat. Genet. 49:249–55
    [Google Scholar]
54. 54.

    Goto K, Lee JH, Matsuda C, Hirabayashi K, Kojo T et al. 1995. DNA rearrangements in Japanese facioscapulohumeral muscular dystrophy patients: clinical correlations. Neuromuscul. Disord. 5:201–8
    [Google Scholar]
55. 55.

    Goto K, Nishino I, Hayashi YK 2004. Very low penetrance in 85 Japanese families with facioscapulohumeral muscular dystrophy 1A. J. Med. Genet. 41:e12
    [Google Scholar]
56. 56.

    Gregory GD, Vakoc CR, Rozovskaia T, Zheng X, Patel S et al. 2007. Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes. Mol. Cell. Biol. 27:8466–79
    [Google Scholar]
57. 57.

    Griggs RC, Tawil R, McDermott M, Forrester J, Figlewicz D, Weiffenbach B (FSH-DY Group). 1995. Monozygotic twins with facioscapulohumeral dystrophy (FSHD): implications for genotype/phenotype correlation. Muscle Nerve 2:S50–55
    [Google Scholar]
58. 58.

    Grolimund L, Aeby E, Hamelin R, Armand F, Chiappe D et al. 2013. A quantitative telomeric chromatin isolation protocol identifies different telomeric states. Nat. Commun. 4:2848
    [Google Scholar]
59. 59.

    Gurzau AD, Chen K, Xue S, Dai W, Lucet IS et al. 2018. FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function. J. Biol. Chem. 293:9841–53
    [Google Scholar]
60. 60.

    Hall LL, Lawrence JB. 2010. XIST RNA and architecture of the inactive X chromosome: implications for the repeat genome. Cold Spring Harb. Symp. Quant. Biol. 75:345–56
    [Google Scholar]
61. 61.

    Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK et al. 1999. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. PNAS 96:14412–17
    [Google Scholar]
62. 62.

    Haynes P, Bomsztyk K, Miller DG 2018. Sporadic DUX4 expression in FSHD myocytes is associated with incomplete repression by the PRC2 complex and gain of H3K9 acetylation on the contracted D4Z4 allele. Epigenet. Chromatin 11:47
    [Google Scholar]
63. 63.

    He F, Todd PK. 2011. Epigenetics in nucleotide repeat expansion disorders. Semin. Neurol 31:470–83
    [Google Scholar]
64. 64.

    Hendrickson PG, Dorais JA, Grow EJ, Whiddon JL, Lim JW et al. 2017. Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nat. Genet. 49:925–34
    [Google Scholar]
65. 65.

    Himeda CL, Debarnot C, Homma S, Beermann ML, Miller JB et al. 2014. Myogenic enhancers regulate expression of the facioscapulohumeral muscular dystrophy associated DUX4 gene. Mol. Cell. Biol. 34:1942–55
    [Google Scholar]
66. 66.

    Himeda CL, Jones TI, Jones PL 2015. Facioscapulohumeral muscular dystrophy as a model for epigenetic regulation and disease. Antioxid. Redox Signal. 22:1463–82
    [Google Scholar]
67. 67.

    Himeda CL, Jones TI, Jones PL 2016. CRISPR/dCas9-mediated transcriptional inhibition ameliorates the epigenetic dysregulation at D4Z4 and represses DUX4-fl in FSH muscular dystrophy. Mol. Ther. 24:527–35
    [Google Scholar]
68. 68.

    Himeda CL, Jones TI, Jones PL 2016. Scalpel or straitjacket: CRISPR/Cas9 approaches for muscular dystrophies. Trends Pharamacol. Sci. 37:249–51
    [Google Scholar]
69. 69.

    Himeda CL, Jones TI, Virbasius CM, Zhu LJ, Green MR, Jones PL 2018. Identification of epigenetic regulators of DUX4-fl for targeted therapy of facioscapulohumeral muscular dystrophy. Mol. Ther. 26:1797–807
    [Google Scholar]
70. 70.

    Homma S, Beermann ML, Boyce FM, Miller JB 2015. Expression of FSHD-related DUX4-FL alters proteostasis and induces TDP-43 aggregation. Ann. Clin. Transl. Neurol. 2:151–66
    [Google Scholar]
71. 71.

    Ivanov AV, Peng H, Yurchenko V, Yap KL, Negorev DG et al. 2007. PHD domain-mediated E3 ligase activity directs intramolecular sumoylation of an adjacent bromodomain required for gene silencing. Mol. Cell 28:823–37
    [Google Scholar]
72. 72.

    Jansz N, Chen K, Murphy JM, Blewitt ME 2017. The epigenetic regulator SMCHD1 in development and disease. Trends Genet 33:233–43
    [Google Scholar]
73. 73.

    Jones TI, Chen JC, Rahimov F, Homma S, Arashiro P et al. 2012. Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis. Hum. Mol. Genet. 21:4419–30
    [Google Scholar]
74. 74.

    Jones TI, Jones PL. 2018. A cre-inducible DUX4 transgenic mouse model for investigating facioscapulohumeral muscular dystrophy. PLOS ONE 13:e0192657
    [Google Scholar]
75. 75.

    Jones TI, King OD, Himeda CL, Homma S, Chen JC et al. 2015. Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy. Clin. Epigenet. 7:37
    [Google Scholar]
76. 76.

    Jones TI, Yan C, Sapp PC, McKenna-Yasek D, Kang PB et al. 2014. Identifying diagnostic DNA methylation profiles for facioscapulohumeral muscular dystrophy in blood and saliva using bisulfite sequencing. Clin. Epigenet. 6:23
    [Google Scholar]
77. 77.

    Kamp C, Hirschmann P, Voss H, Huellen K, Vogt PH 2000. Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events. Hum. Mol. Genet. 9:2563–72
    [Google Scholar]
78. 78.

    Kim KY, Tanaka Y, Su J, Cakir B, Xiang Y et al. 2018. Uhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a. Nat. Commun. 9:2583
    [Google Scholar]
79. 79.

    Klinge L, Eagle M, Haggerty ID, Roberts CE, Straub V, Bushby KM 2006. Severe phenotype in infantile facioscapulohumeral muscular dystrophy. Neuromuscul. Disord. 16:553–58
    [Google Scholar]
80. 80.

    Knopp P, Krom YD, Banerji CR, Panamarova M, Moyle LA et al. 2016. DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis. J. Cell Sci. 129:3816–31
    [Google Scholar]
81. 81.

    Kowaljow V, Marcowycz A, Ansseau E, Conde CB, Sauvage S et al. 2007. The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein. Neuromuscul. Disord. 17:611–23
    [Google Scholar]
82. 82.

    Kulski JK, Gaudieri S, Martin A, Dawkins RL 1999. Coevolution of PERB11 (MIC) and HLA class I genes with HERV-16 and retroelements by extended genomic duplication. J. Mol. Evol. 49:84–97
    [Google Scholar]
83. 83.

    Leidenroth A, Clapp J, Mitchell LM, Coneyworth D, Dearden FL et al. 2012. Evolution of DUX gene macrosatellites in placental mammals. Chromosoma 121:489–97
    [Google Scholar]
84. 84.

    Leidenroth A, Hewitt JE. 2010. A family history of DUX4: phylogenetic analysis of DUXA, B, C and Duxbl reveals the ancestral DUX gene. BMC Evol. Biol 10:364
    [Google Scholar]
85. 85.

    Lemmers RJ, de Kievit P, Sandkuijl L, Padberg GW, van Ommen GJ et al. 2002. Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. Nat. Genet. 32:235–36
    [Google Scholar]
86. 86.

    Lemmers RJ, de Kievit P, van Geel M, van der Wielen MJ, Bakker E et al. 2001. Complete allele information in the diagnosis of facioscapulohumeral muscular dystrophy by triple DNA analysis. Ann. Neurol. 50:816–19
    [Google Scholar]
87. 87.

    Lemmers RJ, Goeman JJ, van der Vliet PJ, Van Nieuwenhuizen MP, Balog J et al. 2015. Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2. Hum. Mol. Genet. 24:659–69
    [Google Scholar]
88. 88.

    Lemmers RJ, Tawil R, Petek LM, Balog J, Block GJ et al. 2012. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat. Genet. 44:1370–74
    [Google Scholar]
89. 89.

    Lemmers RJ, van der Vliet PJ, Balog J, Goeman JJ, Arindrarto W et al. 2018. Deep characterization of a common D4Z4 variant identifies biallelic DUX4 expression as a modifier for disease penetrance in FSHD2. Eur. J. Hum. Genet. 26:94–106
    [Google Scholar]
90. 90.

    Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camano P et al. 2010. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science 329:1650–53
    [Google Scholar]
91. 91.

    Lemmers RJ, van der Vliet PJ, van der Gaag KJ, Zuniga S, Frants RR et al. 2010. Worldwide population analysis of the 4q and 10q subtelomeres identifies only four discrete interchromosomal sequence transfers in human evolution. Am. J. Hum. Genet. 86:364–77
    [Google Scholar]
92. 92.

    Lemmers RJ, van der Vliet PJ, Vreijling JP, Henderson D, van der Stoep N et al. 2018. Cis D4Z4 repeat duplications associated with facioscapulohumeral muscular dystrophy type 2. Hum. Mol. Genet. 27:3488–97
    [Google Scholar]
93. 93.

    Lemmers RJ, Wohlgemuth M, Frants RR, Padberg GW, Morava E, van der Maarel SM 2004. Contractions of D4Z4 on 4qB subtelomeres do not cause facioscapulohumeral muscular dystrophy. Am. J. Hum. Genet. 75:1124–30
    [Google Scholar]
94. 94.

    Lemmers RJ, Wohlgemuth M, van der Gaag KJ, van der Vliet PJ, van Teijlingen CM et al. 2007. Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy. Am. J. Hum. Genet. 81:884–94
    [Google Scholar]
95. 95.

    Lim JW, Snider L, Yao Z, Tawil R, van der Maarel SM et al. 2015. DICER/AGO-dependent epigenetic silencing of D4Z4 repeats enhanced by exogenous siRNA suggests mechanisms and therapies for FSHD. Hum. Mol. Genet. 24:4817–28
    [Google Scholar]
96. 96.

    Lunt PW, Jardine PE, Koch MC, Maynard J, Osborn M et al. 1995. Correlation between fragment size at D4F104S1 and age at onset or at wheelchair use, with a possible generational effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD). Hum. Mol. Genet. 4:951–58
    [Google Scholar]
97. 97.

    Lunt PW, Jardine PE, Koch MC, Maynard J, Osborn M et al. 1995. Phenotypic-genotypic correlation will assist genetic counseling in 4q35-facioscapulohumeral muscular dystrophy. Muscle Nerve 2:S103–9
    [Google Scholar]
98. 98.

    Macfarlan TS, Gifford WD, Agarwal S, Driscoll S, Lettieri K et al. 2011. Endogenous retroviruses and neighboring genes are coordinately repressed by LSD1/KDM1A. Genes Dev 25:594–607
    [Google Scholar]
99. 99.

    Maison C, Bailly D, Roche D, Montes de Oca R, Probst AV et al. 2011. SUMOylation promotes de novo targeting of HP1α to pericentric heterochromatin. Nat. Genet. 43:220–27
    [Google Scholar]
100. 100.

     Marsollier AC, Ciszewski L, Mariot V, Popplewell L, Voit T et al. 2016. Antisense targeting of 3′ end elements involved in DUX4 mRNA processing is an efficient therapeutic strategy for facioscapulohumeral dystrophy: a new gene-silencing approach. Hum. Mol. Genet. 25:1468–78
     [Google Scholar]
101. 101.

     Mason AG, Slieker RC, Balog J, Lemmers RJ, Wong CJ et al. 2017. SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes. Skelet. Muscle 7:12
     [Google Scholar]
102. 102.

     Mitsuhashi H, Mitsuhashi S, Lynn-Jones T, Kawahara G, Kunkel LM 2013. Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Hum. Mol. Genet. 22:568–77
     [Google Scholar]
103. 103.

     Mitsuhashi S, Boyden SE, Estrella EA, Jones TI, Rahimov F et al. 2013. Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral muscular dystrophy 2. Neuromuscul. Disord. 23:975–80
     [Google Scholar]
104. 104.

     Miyazaki H, Higashimoto K, Yada Y, Endo TA, Sharif J et al. 2013. Ash1l methylates Lys36 of histone H3 independently of transcriptional elongation to counteract Polycomb silencing. PLOS Genet 9:e1003897
     [Google Scholar]
105. 105.

     Mould AW, Pang Z, Pakusch M, Tonks ID, Stark M et al. 2013. Smchd1 regulates a subset of autosomal genes subject to monoallelic expression in addition to being critical for X inactivation. Epigenet. Chromatin 6:19
     [Google Scholar]
106. 106.

     Mul K, Lemmers RJ, Kriek M, van der Vliet PJ, van den Boogaard ML et al. 2018. FSHD type 2 and Bosma arhinia microphthalmia syndrome: two faces of the same mutation. Neurology 91:e562–70
     [Google Scholar]
107. 107.

     Mul K, Voermans NC, Lemmers RJ, Jonker MA, van der Vliet PJ et al. 2018. Phenotype-genotype relations in facioscapulohumeral muscular dystrophy type 1. Clin. Genet. 94:521–27
     [Google Scholar]
108. 108.

     Nguyen K, Puppo F, Roche S, Gaillard MC, Chaix C et al. 2017. Molecular combing reveals complex 4q35 rearrangements in facioscapulohumeral dystrophy. Hum. Mutat. 38:1432–41
     [Google Scholar]
109. 109.

     Nguyen K, Walrafen P, Bernard R, Attarian S, Chaix C et al. 2011. Molecular combing reveals allelic combinations in facioscapulohumeral dystrophy. Ann. Neurol. 70:627–33
     [Google Scholar]
110. 110.

     Nozawa RS, Nagao K, Igami KT, Shibata S, Shirai N et al. 2013. Human inactive X chromosome is compacted through a PRC2-independent SMCHD1-HBiX1 pathway. Nat. Struct. Mol. Biol. 20:566–73
     [Google Scholar]
111. 111.

     Orphanet 2018. Prevalence and incidence of rare diseases: bibliographic data Orphanet Rep. Ser., June, No. 1 Inserm Paris:
112. 112.

     Orr HT, Zoghbi HY. 2007. Trinucleotide repeat disorders. Annu. Rev. Neurosci. 30:575–621
     [Google Scholar]
113. 113.

     Padberg GW. 1982. Facioscapulohumeral disease PhD Thesis, Leiden Univ., Leiden, Neth .
114. 114.

     Padberg GW, van Engelen BG 2009. Facioscapulohumeral muscular dystrophy. Curr. Opin. Neurol. 22:539–42
     [Google Scholar]
115. 115.

     Peart N, Wagner EJ. 2017. A distal auxiliary element facilitates cleavage and polyadenylation of Dux4 mRNA in the pathogenic haplotype of FSHD. Hum. Genet. 136:1291–301
     [Google Scholar]
116. 116.

     Rakyan VK, Blewitt ME, Druker R, Preis JI, Whitelaw E 2002. Metastable epialleles in mammals. Trends Genet 18:348–51
     [Google Scholar]
117. 117.

     Ramesh V, Bayam E, Cernilogar FM, Bonapace IM, Schulze M et al. 2016. Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration. Genes Dev 30:2199–212
     [Google Scholar]
118. 118.

     Rearden A, Magnet A, Kudo S, Fukuda M 1993. Glycophorin B and glycophorin E genes arose from the glycophorin A ancestral gene via two duplications during primate evolution. J. Biol. Chem. 268:2260–67
     [Google Scholar]
119. 119.

     Ricci E, Galluzzi G, Deidda G, Cacurri S, Colantoni L et al. 1999. Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype. Ann. Neurol. 45:751–57
     [Google Scholar]
120. 120.

     Ricci G, Scionti I, Sera F, Govi M, D'Amico R et al. 2013. Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy. Brain 136:3408–17
     [Google Scholar]
121. 121.

     Rickard AM, Petek LM, Miller DG 2015. Endogenous DUX4 expression in FSHD myotubes is sufficient to cause cell death and disrupts RNA splicing and cell migration pathways. Hum. Mol. Genet. 24:5901–14
     [Google Scholar]
122. 122.

     Rossi M, Ricci E, Colantoni L, Galluzzi G, Frusciante R et al. 2007. The Facioscapulohumeral muscular dystrophy region on 4qter and the homologous locus on 10qter evolved independently under different evolutionary pressure. BMC Med. Genet. 8:8
     [Google Scholar]
123. 123.

     Rothbart SB, Krajewski K, Nady N, Tempel W, Xue S et al. 2012. Association of UHRF1 with methylated H3K9 directs the maintenance of DNA methylation. Nat. Struct. Mol. Biol. 19:1155–60
     [Google Scholar]
124. 124.

     Sacconi S, Lemmers RJ, Balog J, van der Vliet PJ, Lahaut P et al. 2013. The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am. J. Hum. Genet. 93:744–51
     [Google Scholar]
125. 125.

     Sakellariou P, Kekou K, Fryssira H, Sofocleous C, Manta P et al. 2012. Mutation spectrum and phenotypic manifestation in FSHD Greek patients. Neuromuscul. Disord. 22:339–49
     [Google Scholar]
126. 126.

     Scionti I, Greco F, Ricci G, Govi M, Arashiro P et al. 2012. Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy. Am. J. Hum. Genet. 90:628–35
     [Google Scholar]
127. 127.

     Shadle SC, Zhong JW, Campbell AE, Conerly ML, Jagannathan S et al. 2017. DUX4-induced dsRNA and MYC mRNA stabilization activate apoptotic pathways in human cell models of facioscapulohumeral dystrophy. PLOS Genet 13:e1006658
     [Google Scholar]
128. 128.

     Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A et al. 2007. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450:908–12
     [Google Scholar]
129. 129.

     Shaw ND, Brand H, Kupchinsky ZA, Bengani H, Plummer L et al. 2017. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat. Genet. 49:238–48
     [Google Scholar]
130. 130.

     Snider L, Geng LN, Lemmers RJ, Kyba M, Ware CB et al. 2010. Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLOS Genet 6:e1001181
     [Google Scholar]
131. 131.

     Tawil R, Forrester J, Griggs RC, Mendell J, Kissel J et al. (FSH-DY Group). 1996. Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. Ann. Neurol. 39:744–48
     [Google Scholar]
132. 132.

     Tawil R, van der Maarel SM 2006. Facioscapulohumeral muscular dystrophy. Muscle Nerve 34:1–15
     [Google Scholar]
133. 133.

     Tawil R, van der Maarel SM, Tapscott SJ 2014. Facioscapulohumeral dystrophy: the path to consensus on pathophysiology. Skelet. Muscle 4:12
     [Google Scholar]
134. 134.

     Tirard M, Hsiao HH, Nikolov M, Urlaub H, Melchior F, Brose N 2012. In vivo localization and identification of SUMOylated proteins in the brain of His6-HA-SUMO1 knock-in mice. PNAS 109:21122–27
     [Google Scholar]
135. 135.

     Tonini MM, Passos-Bueno MR, Cerqueira A, Matioli SR, Pavanello R, Zatz M 2004. Asymptomatic carriers and gender differences in facioscapulohumeral muscular dystrophy (FSHD). Neuromuscul. Disord. 14:33–38
     [Google Scholar]
136. 136.

     Trombetta B, Fantini G, D'Atanasio E, Sellitto D, Cruciani F 2016. Evidence of extensive non-allelic gene conversion among LTR elements in the human genome. Sci. Rep. 6:28710
     [Google Scholar]
137. 137.

     Tupler R, Barbierato L, Memmi M, Sewry CA, De Grandis D et al. 1998. Identical de novo mutation at the D4F104S1 locus in monozygotic male twins affected by facioscapulohumeral muscular dystrophy (FSHD) with different clinical expression. J. Med. Genet. 35:778–83
     [Google Scholar]
138. 138.

     van den Boogaard ML, Lemmers RJ, Balog J, Wohlgemuth M, Auranen M et al. 2016. Mutations in DNMT3B modify epigenetic repression of the D4Z4 repeat and the penetrance of facioscapulohumeral dystrophy. Am. J. Hum. Genet. 98:1020–29
     [Google Scholar]
139. 139.

     van der Maarel SM, Frants RR, Padberg GW 2007. Facioscapulohumeral muscular dystrophy. Biochim. Biophys. Acta 1772:186–94
     [Google Scholar]
140. 140.

     van Deutekom JC, Bakker E, Lemmers RJ, van der Wielen MJ, Bik E et al. 1996. Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1. Hum. Mol. Genet. 5:1997–2003
     [Google Scholar]
141. 141.

     van Deutekom JC, Wijmenga C, van Tienhoven EA, Gruter AM, Hewitt JE et al. 1993. FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum. Mol. Genet. 2:2037–42
     [Google Scholar]
142. 142.

     van Overveld PG, Enthoven L, Ricci E, Rossi M, Felicetti L et al. 2005. Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy. Ann. Neurol. 58:569–76
     [Google Scholar]
143. 143.

     van Overveld PG, Lemmers RJ, Sandkuijl LA, Enthoven L, Winokur ST et al. 2003. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat. Genet. 35:315–17
     [Google Scholar]
144. 144.

     Vasale J, Boyar F, Jocson M, Sulcova V, Chan P et al. 2015. Molecular combing compared to Southern blot for measuring D4Z4 contractions in FSHD. Neuromuscul. Disord. 25:945–51
     [Google Scholar]
145. 145.

     Wallace LM, Garwick SE, Mei W, Belayew A, Coppee F et al. 2011. DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo. Ann. Neurol. 69:540–52
     [Google Scholar]
146. 146.

     Wallace LM, Liu J, Domire JS, Garwick-Coppens SE, Guckes SM et al. 2012. RNA interference inhibits DUX4-induced muscle toxicity in vivo: implications for a targeted FSHD therapy. Mol. Ther. 20:1417–23
     [Google Scholar]
147. 147.

     Whiddon JL, Langford AT, Wong CJ, Zhong JW, Tapscott SJ 2017. Conservation and innovation in the DUX4-family gene network. Nat. Genet. 49:935–40
     [Google Scholar]
148. 148.

     Wijmenga C, Frants RR, Brouwer OF, Moerer P, Weber JL, Padberg GW 1990. Location of facioscapulohumeral muscular dystrophy gene on chromosome 4. Lancet 336:651–53
     [Google Scholar]
149. 149.

     Wijmenga C, Frants RR, Hewitt JE, van Deutekom JC, van Geel M et al. 1993. Molecular genetics of facioscapulohumeral muscular dystrophy. Neuromuscul. Disord. 3:487–91
     [Google Scholar]
150. 150.

     Wijmenga C, Hewitt JE, Sandkuijl LA, Clark LN, Wright TJ et al. 1992. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat. Genet. 2:26–30
     [Google Scholar]
151. 151.

     Winston J, Duerden L, Mort M, Frayling IM, Rogers MT, Upadhyaya M 2015. Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy. Eur. J. Hum. Genet. 23:67–71
     [Google Scholar]
152. 152.

     Wohlgemuth M, Lemmers RJ, van der Kooi EL, van der Wielen MJ, van Overveld PG et al. 2003. Possible phenotypic dosage effect in patients compound heterozygous for FSHD-sized 4q35 alleles. Neurology 61:909–13
     [Google Scholar]
153. 153.

     Wuebbles RD, Long SW, Hanel ML, Jones PL 2010. Testing the effects of FSHD candidate gene expression in vertebrate muscle development. Int. J. Clin. Exp. Pathol. 3:386–400
     [Google Scholar]
154. 154.

     Xi Z, Zinman L, Moreno D, Schymick J, Liang Y et al. 2013. Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am. J. Hum. Genet. 92:981–89
     [Google Scholar]
155. 155.

     Xu GL, Bestor TH, Bourc'his D, Hsieh CL, Tommerup N et al. 1999. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402:187–91
     [Google Scholar]
156. 156.

     Yan Y, Buckler-White A, Wollenberg K, Kozak CA 2009. Origin, antiviral function and evidence for positive selection of the gammaretrovirus restriction gene Fv1 in the genus Mus. . PNAS 106:3259–63
     [Google Scholar]
157. 157.

     Yao Z, Snider L, Balog J, Lemmers RJ, Van der Maarel SM et al. 2014. DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle. Hum. Mol. Genet. 23:5342–52
     [Google Scholar]
158. 158.

     Young JM, Whiddon JL, Yao Z, Kasinathan B, Snider L et al. 2013. DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis. PLOS Genet 9:e1003947
     [Google Scholar]
159. 159.

     Zatz M, Marie SK, Cerqueira A, Vainzof M, Pavanello RC, Passos-Bueno MR 1998. The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females. Am. J. Med. Genet. 77:155–61
     [Google Scholar]
160. 160.

     Zatz M, Marie SK, Passos-Bueno MR, Vainzof M, Campiotto S et al. 1995. High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families. Am. J. Hum. Genet. 56:99–105
     [Google Scholar]
161. 161.

     Zeng W, Chen YY, Newkirk DA, Wu B, Balog J et al. 2014. Genetic and epigenetic characteristics of FSHD-associated 4q and 10q D4Z4 that are distinct from non-4q/10q D4Z4 homologs. Hum. Mutat. 35:998–1010
     [Google Scholar]
162. 162.

     Zeng W, de Greef JC, Chen YY, Chien R, Kong X et al. 2009. Specific loss of histone H3 lysine 9 trimethylation and HP1γ/cohesin binding at D4Z4 repeats is associated with facioscapulohumeral dystrophy (FSHD). PLOS Genet 5:e1000559
     [Google Scholar]
163. 163.

     Zhang Y, Forner J, Fournet S, Jeanpierre M 2001. Improved characterization of FSHD mutations. Ann. Genet. 44:105–10
     [Google Scholar]