Medicine Genetics Group, Vall d'Hebron Research Institute (VHIR), 08035 Barcelona, Spain.
Department of Clinical and Molecular Genetics, Hospital Vall d'Hebron, 08035 Barcelona, Spain.
Int J Mol Sci. 2021 Aug 21;22(16):9029. doi: 10.3390/ijms22169029.
After 26 years of discovery of the determinant survival motor neuron 1 and the modifier survival motor neuron 2 genes ( and , respectively), three SMN-dependent specific therapies are already approved by FDA and EMA and, as a consequence, worldwide SMA patients are currently under clinical investigation and treatment. Bi-allelic pathogenic variants (mostly deletions) in should be detected in SMA patients to confirm the disease. Determination of copy number has been historically employed to correlate with the phenotype, predict disease evolution, stratify patients for clinical trials and to define those eligible for treatment. In view that discordant genotype-phenotype correlations are present in SMA, besides technical issues with detection of copy number, we have hypothesized that copy number determination is only the tip of the iceberg and that more deepen studies of variants, sequencing and structures of the genes are necessary for a better understanding of the disease as well as to investigate possible influences in treatment responses. Here, we highlight the importance of a comprehensive approach of and genetics with the perspective to apply for better prediction of SMA in positive neonatal screening cases and early diagnosis to start treatments.
在发现决定生存运动神经元 1 和修饰生存运动神经元 2 基因（分别为和）后的 26 年，三种依赖 SMN 的特异性疗法已经获得 FDA 和 EMA 的批准，因此，全球范围内的 SMA 患者目前正在接受临床研究和治疗。SMA 患者应检测到双等位致病性变异（主要为缺失）以确认疾病。为了与表型相关联，预测疾病进展，对临床试验进行分层，并确定有治疗资格的患者，历史上一直采用确定拷贝数。鉴于 SMA 中存在不一致的基因型-表型相关性，除了检测拷贝数的技术问题外，我们假设拷贝数确定只是冰山一角，需要对变体、测序和进行更深入的研究，以更好地了解疾病，并研究治疗反应中可能存在的影响。在这里，我们强调了综合方法的重要性，即和遗传学的综合方法，以期更好地预测新生儿筛查阳性病例中的 SMA，并进行早期诊断以开始治疗。
