Lemmers Richard J L F, van den Boogaard Marlinde L, van der Vliet Patrick J, Donlin-Smith Colleen M, Nations Sharon P, Ruivenkamp Claudia A L, Heard Patricia, Bakker Bert, Tapscott Stephen, Cody Jannine D, Tawil Rabi, van der Maarel Silvère M
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Neuromuscular Disease Unit, Department of Neurology, University of Rochester Medical Center, Rochester, New York.
Hum Mutat. 2015 Jul;36(7):679-83. doi: 10.1002/humu.22792. Epub 2015 May 20.
Facioscapulohumeral muscular dystrophy (FSHD) is most often associated with variegated expression in somatic cells of the normally repressed DUX4 gene within the D4Z4-repeat array. The most common form, FSHD1, is caused by a D4Z4-repeat array contraction to a size of 1-10 units (normal range 10-100 units). The less common form, FSHD2, is characterized by D4Z4 CpG hypomethylation and is most often caused by loss-of-function mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene on chromosome 18p. The chromatin modifier SMCHD1 is necessary to maintain a repressed D4Z4 chromatin state. Here, we describe two FSHD2 families with a 1.2-Mb deletion encompassing the SMCHD1 gene. Numerical aberrations of chromosome 18 are relatively common and the majority of 18p deletion syndrome (18p-) cases have, such as these FSHD2 families, only one copy of SMCHD1. Our finding therefore raises the possibility that 18p- cases are at risk of developing FSHD. To address this possibility, we combined genome-wide array analysis data with D4Z4 CpG methylation and repeat array sizes in individuals with 18p- and conclude that approximately 1:8 18p- cases might be at risk of developing FSHD.
面肩肱型肌营养不良症（FSHD）通常与D4Z4重复序列阵列中正常情况下被抑制的DUX4基因在体细胞中的多样化表达有关。最常见的形式是FSHD1，由D4Z4重复序列阵列收缩至1 - 10个单位大小（正常范围为10 - 100个单位）引起。较不常见的形式是FSHD2，其特征是D4Z4 CpG低甲基化，最常见的原因是18号染色体短臂上的染色体结构维持铰链域1（SMCHD1）基因功能丧失突变。染色质修饰因子SMCHD1对于维持D4Z4染色质的抑制状态是必需的。在这里，我们描述了两个FSHD2家系，其存在一个包含SMCHD1基因的1.2兆碱基缺失。18号染色体的数目畸变相对常见，并且大多数18号染色体短臂缺失综合征（18p-）病例，如这些FSHD2家系，只有一个SMCHD1拷贝。因此，我们的发现增加了18p-病例有患FSHD风险的可能性。为了探究这种可能性，我们将全基因组阵列分析数据与18p-个体的D4Z4 CpG甲基化和重复序列阵列大小相结合，得出结论：大约1/8的18p-病例可能有患FSHD的风险。
