Biochemistry Department, Tulane Medical School, New Orleans, Louisiana, USA.
J Med Genet. 2010 Nov;47(11):745-51. doi: 10.1136/jmg.2009.076703. Epub 2010 Aug 15.
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease associated with contraction of arrays of tandem 3.3-kb units (D4Z4) on subtelomeric 4q. Disease-linked arrays usually have fewer than 11 repeat units. Equally short D4Z4 arrays at subtelomeric 10q are not linked to FSHD. The newly described 4qA161 haplotype, which is more prevalent in pathogenic 4q alleles, involves sequences in and near D4Z4.
We developed two new assays for 4qA161, which are based upon direct sequencing of PCR products or detecting restriction fragment length polymorphisms. They were used to analyse single nucleotide polymorphisms (SNPs) indicative of 4q161 alleles.
All (35/35) FSHD patients had one or two 4qA161 alleles (60% or 40%, respectively). In contrast, 46% (21/46) of control individuals had no 4qA161 allele (p<10(-4)), and 26% had homozygous 4qB163 alleles.
Our results from a heterogeneous population are consistent with the previously described association of the 4qA161 haplotype with FSHD, but a causal association with pathogenesis is uncertain. In addition, we found that haplotype analysis is complicated by the presence of minor 10q alleles. Nonetheless, our sequencing assay for the 4qA161allele can enhance molecular diagnosis of FSHD, including prenatal diagnosis, and is simpler to perform than the previously described assay.
面肩肱型肌营养不良症（FSHD）是一种常染色体显性疾病，与端粒上 4q 的串联 3.3kb 单位（D4Z4）收缩有关。与疾病相关的阵列通常少于 11 个重复单位。端粒上 10q 的同样短的 D4Z4 阵列与 FSHD 无关。新描述的 4qA161 单倍型在致病 4q 等位基因中更为常见，涉及 D4Z4 内和附近的序列。
我们开发了两种新的 4qA161 检测方法，它们基于 PCR 产物的直接测序或检测限制性片段长度多态性。它们用于分析指示 4q161 等位基因的单核苷酸多态性（SNP）。
所有（35/35）FSHD 患者均具有一个或两个 4qA161 等位基因（分别为 60%或 40%）。相比之下，46%（21/46）的对照组个体没有 4qA161 等位基因（p<10(-4)），26%为纯合的 4qB163 等位基因。
我们在异质人群中的结果与先前描述的 4qA161 单倍型与 FSHD 的关联一致，但与发病机制的因果关联尚不确定。此外，我们发现，单倍型分析因存在次要的 10q 等位基因而变得复杂。尽管如此，我们用于 4qA161 等位基因的测序检测可以增强 FSHD 的分子诊断，包括产前诊断，并且比以前描述的检测方法更简单。
