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首页> 外文期刊>Human mutation >Beyond copy number: A new, rapid, and versatile method for sequencing the entire SMN2 gene in SMA patients
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Beyond copy number: A new, rapid, and versatile method for sequencing the entire SMN2 gene in SMA patients

机译：超越拷贝数：用于测序SMA患者的整个SMN2基因的新的，快速和多功能的方法

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摘要

Spinal muscular atrophy (SMA) is caused by bi-allelic loss or pathogenic variants in the SMN1 gene. SMN2, the highly homologous copy of SMN1, is considered the major phenotypic modifier of the disease. Determination of SMN2 copy number is essential to establish robust genotype-phenotype correlations and predict disease evolution, to stratify patients for clinical trials, as well as to define those eligible for treatment. Discordant genotype-phenotype correlations are not uncommon in SMA, some of which are due to intragenic SMN2 variants that may influence the amount of complete SMN transcripts and, therefore, of full-length SMN protein. Detection of these variants is crucial to predict SMA phenotypes in the present scenario of therapeutic advances and with the perspective of SMA neonatal screening and early diagnosis to start treatments. Here, we present a novel, affordable, and versatile method for complete sequencing of the SMN2 gene based on long-range polymerase chain reaction and next-generation sequencing. The method was validated by analyzing samples from 53 SMA patients who lack SMN1, allowing to characterize paralogous, rare variants, and single-nucleotide polymorphisms of SMN2 as well as SMN2-SMN1 hybrid genes. The method identifies partial deletions and can be adapted to determine rare pathogenic variants in patients with at least one SMN1 copy.
机译：脊髓性肌萎缩（SMA）是由SMN1基因的双等位基因缺失或致病性变体引起的。SMN2是SMN1的高度同源拷贝，被认为是该疾病的主要表型修饰因子。SMN2拷贝数的测定对于建立可靠的基因型-表型相关性和预测疾病演变、对患者进行临床试验分层以及确定符合治疗条件的患者至关重要。不一致的基因型-表型相关性在SMA中并不少见，其中一些是由于基因内SMN2变异引起的，这些变异可能影响完整SMN转录本的数量，从而影响全长SMN蛋白的数量。在目前治疗进展的情况下，从SMA新生儿筛查和早期诊断的角度出发，检测这些变异对于预测SMA表型至关重要。在这里，我们提出了一种基于远程聚合酶链反应和下一代测序的SMN2基因完整测序的新颖、廉价且通用的方法。通过分析53例缺乏SMN1的SMA患者的样本，验证了该方法的有效性，从而能够描述SMN2以及SMN2-SMN1杂交基因的同源、罕见变异和单核苷酸多态性。该方法可识别部分缺失，并可适用于确定至少有一个SMN1拷贝的患者中的罕见致病性变体。

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