摘要
面肩肱型肌营养不良症(FSHD)被归类为常染色体显性遗传病,在位于4q亚端粒(4q35)的一批重组3.3 kb衔接着重复DNA元素(D4Z4)。在过去的20年中,FSHD的诊断在临床实践中已被证实,可通过一个D4Z4等位基因在4q35重复的检测数量减少(≤8)。虽然广泛的家庭间和家庭内的临床变异被发现受试者携带缩小尺寸的D4Z4等位基因,这个DNA测试已经被认为是高度敏感的和专一的。然而,在这个普遍规则之外的几个例外已经被报道。具体来说,FSHD家庭中无症状的亲戚携带等位基因减少的D4Z4,并描述了FSHD家谱中影响其他神经肌肉疾病和携带正常尺度的D4Z4等位基因的FSHD感染病人。为了解释这些发现,已经提出了在4q35重复的D4Z4减少可能仅在某些染色体背景下致病,定义为“许可”的特定的单倍型。然而,我们最近的研究表明,FSHD的当前DNA的特征是一个常见的多态性,对于D4Z4减少等位基因(DRA)的携带者发展成为FSHD的风险取决于除4q35基因位点之外的其他附加因素。这些发现强调了重新评估的必要性和DRA预测值的意义,不仅用于研究,而且在临床实践中。针对FSHD家庭的进一步的临床和遗传分析为剖析FSHD复杂性的研究将是非常重要。
关键词: D4Z4等位基因减少,诊断标准,面肩肱型肌营养不良症,遗传咨询,遗传异质性,基因型-表现型相关,分子测试,肌肉疾病。
Current Molecular Medicine
Title:Facioscapulohumeral Muscular Dystrophy: More Complex than it Appears
Volume: 14 Issue: 8
Author(s): G. Ricci, M. Zatz and R. Tupler
Affiliation:
关键词: D4Z4等位基因减少,诊断标准,面肩肱型肌营养不良症,遗传咨询,遗传异质性,基因型-表现型相关,分子测试,肌肉疾病。
摘要: Facioscapulohumeral muscular dystrophy (FSHD) has been classified as an autosomal dominant myopathy, linked to rearrangements in an array of 3.3 kb tandemly repeated DNA elements (D4Z4) located at the 4q subtelomere (4q35). For the last 20 years, the diagnosis of FSHD has been confirmed in clinical practice by the detection of one D4Z4 allele with a reduced number (≤8) of repeats at 4q35. Although wide inter- and intra-familial clinical variability was found in subjects carrying D4Z4 alleles of reduced size, this DNA testing has been considered highly sensitive and specific. However, several exceptions to this general rule have been reported. Specifically, FSHD families with asymptomatic relatives carrying D4Z4 reduced alleles, FSHD genealogies with subjects affected with other neuromuscular disorders and FSHD affected patients carrying D4Z4 alleles of normal size have been described. In order to explain these findings, it has been proposed that the reduction of D4Z4 repeats at 4q35 could be pathogenic only in certain chromosomal backgrounds, defined as “permissive” specific haplotypes. However, our most recent studies show that the current DNA signature of FSHD is a common polymorphism and that in FSHD families the risk of developing FSHD for carriers of D4Z4 reduced alleles (DRA) depends on additional factors besides the 4q35 locus. These findings highlight the necessity to re-evaluate the significance and the predictive value of DRA, not only for research but also in clinical practice. Further clinical and genetic analysis of FSHD families will be extremely important for studies aiming at dissecting the complexity of FSHD.
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Cite this article as:
Ricci G., Zatz M. and Tupler R., Facioscapulohumeral Muscular Dystrophy: More Complex than it Appears, Current Molecular Medicine 2014; 14 (8) . https://dx.doi.org/10.2174/1566524014666141010155054
DOI https://dx.doi.org/10.2174/1566524014666141010155054 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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