van Deutekom J C, Bakker E, Lemmers R J, van der Wielen M J, Bik E, Hofker M H, Padberg G W, Frants R R
MGC-Department of Human Genetics, Sylvius Laboratory, Leiden University, The Netherlands.
Hum Mol Genet. 1996 Dec;5(12):1997-2003. doi: 10.1093/hmg/5.12.1997.
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy, clinically characterized by asymmetric weakness of muscles in the face, shoulder girdle and upper arm. Deletion of an integral number of 3.3 kb repeated units within a highly polymorphic EcoRI fragment at chromosome 4q35, generating a relatively short EcoRI fragment (< 35 kb), has been shown to cause FSHD1. Probe p13E-11 detects these short fragments in FSHD1 patients, and has therefore been used for diagnostic DNA analysis. However, the reliability of this analysis has been hampered by cross-hybridization of p13E-11 to chromosome 10q26-linked EcoRI fragments of comparable size, which also contain a variable number of 3.3 kb repeated units. Recently, a BinI restriction site was identified within each of the repeated units derived from chromosome 10q26, which enables differentiation of the two polymorphic p13E-11 loci in most cases without haplotype analysis. Remarkably, applying the differential analysis to screen DNA of 160 Dutch cases referred to us for FSHD1 diagnosis, we obtained evidence for subtelomeric exchange of 3.3 kb repeated units between chromosomes 4q35 and 10q26 in affected and unaffected individuals. Subsequently, analysis of 50 unrelated control samples indicated such exchange between chromosomes 4q35 and 10q26 in at least 20% of the population. These subtelomeric rearrangements have generated a novel interchromosomal polymorphism, which has implications for the specificity and sensitivity of the differential restriction analysis for diagnostic purposes. Moreover, the high frequency of the interchromosomal exchanges of 3.3 kb repeated units suggests that they probably do not contain (part of) the FSHD1 gene, and supports position effect variegation as the most likely mechanism for FSHD1.
面肩肱型肌营养不良症（FSHD）是一种常染色体显性肌病，临床特征为面部、肩胛带和上臂肌肉不对称性无力。已证实，在染色体4q35上一个高度多态性的EcoRI片段内缺失整数个3.3 kb重复单位，产生一个相对较短的EcoRI片段（< 35 kb），可导致FSHD1型疾病。探针p13E - 11可检测FSHD1型患者中的这些短片段，因此已用于诊断性DNA分析。然而，该分析的可靠性受到p13E - 11与10q26染色体上大小相当的EcoRI片段交叉杂交的阻碍，这些片段也包含可变数量的3.3 kb重复单位。最近，在源自10q26染色体的每个重复单位内鉴定出一个BinI限制性位点，这使得在大多数情况下无需单倍型分析就能区分两个多态性p13E - 11位点。值得注意的是，应用差异分析筛选转介给我们进行FSHD1诊断的160例荷兰患者的DNA时，我们获得证据表明，在患病和未患病个体中，染色体4q35和10q26之间存在3.3 kb重复单位的亚端粒交换。随后，对50个无关对照样本的分析表明，至少20%的人群中染色体4q35和10q26之间存在这种交换。这些亚端粒重排产生了一种新的染色体间多态性，这对用于诊断目的的差异限制性分析的特异性和敏感性具有影响。此外，3.3 kb重复单位染色体间交换的高频率表明它们可能不包含FSHD1基因（的部分），并支持位置效应斑驳作为FSHD1最可能的发病机制。
