Practical guidelines to manage discordant situations of SMN2 copy number in patients with spinal muscular atrophy.
Practical guidelines to manage discordant situations of SMN2 copy number in patients with spinal muscular atrophy.
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DOI：
10.1212/nxg.0000000000000530
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Tizzano EF
中科院分区：
文献类型：
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作者：
Cuscó I;Bernal S;Blasco-Pérez L;Calucho M;Alias L;Fuentes-Prior P;Tizzano EF
评估脊髓性肌萎缩症（SMA）患者的SMN 2拷贝数对于建立仔细的基因型-表型相关性和预测疾病进展至关重要。从SMA新生儿筛查和早期诊断以启动治疗的角度来看，这个问题在目前的治疗进展中变得至关重要，因为这个值对于临床试验的患者分层和确定有资格接受药物治疗的患者至关重要。一些技术缺陷和个体间变异可能导致SMN 2拷贝数估计和表型-基因型相关性建立的差异。我们提出了一个管理指南的基础上一系列指定的行动，一旦SMN 2拷贝数确定为给定的患者。无论使用何种方法来估计SMN 2拷贝数，我们的方法都侧重于患者的表现，以建议如何在每种情况下进行。我们根据症状前筛查情景中的SMN 2拷贝数定义了情况，在这种情况下，我们预测了可能的演变，并且当有症状的患者被遗传学证实时。非预期不一致病例包括具有单个SMN 2拷贝但非先天性疾病形式、2个SMN 2拷贝与II型或III型SMA相容以及3个或4个基因拷贝显示疾病比预期更严重的患者。我们提出的指南将有助于系统地识别需要进一步遗传学研究的不一致SMA病例。SMN 2基因作为SMA表型的主要修饰基因，值得更深入的研究，以提供更准确的基因型-表型相关性。
Assessment of SMN2 copy number in patients with spinal muscular atrophy (SMA) is essential to establish careful genotype-phenotype correlations and predict disease evolution. This issue is becoming crucial in the present scenario of therapeutic advances with the perspective of SMA neonatal screening and early diagnosis to initiate treatment, as this value is critical to stratify patients for clinical trials and to define those eligible to receive medication. Several technical pitfalls and interindividual variations may account for reported discrepancies in the estimation of SMN2 copy number and establishment of phenotype-genotype correlations. We propose a management guide based on a sequence of specified actions once SMN2 copy number is determined for a given patient. Regardless of the method used to estimate the number of SMN2 copies, our approach focuses on the manifestations of the patient to recommend how to proceed in each case. We defined situations according to SMN2 copy number in a presymptomatic scenario of screening, in which we predict the possible evolution, and when a symptomatic patient is genetically confirmed. Unexpected discordant cases include patients having a single SMN2 copy but noncongenital disease forms, 2 SMN2 copies compatible with type II or III SMA, and 3 or 4 copies of the gene showing more severe disease than expected. Our proposed guideline would help to systematically identify discordant SMA cases that warrant further genetic investigation. The SMN2 gene, as the main modifier of SMA phenotype, deserves a more in-depth study to provide more accurate genotype-phenotype correlations.