Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Gene Editing of Human Genetic Disease, Jianshe Rd, Erqi District, Zhengzhou, Henan, 450052, People's Republic of China.
Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou Children's Hospital, No-33, Longhu Waihuan East Road, Zhengzhou, He Nan Province, 450018, People's Republic of China.
Eur J Med Genet. 2020 Sep;63(9):104006. doi: 10.1016/j.ejmg.2020.104006. Epub 2020 Jul 10.
Spinal muscular atrophy (SMA) is a common autosomal recessive genetic disorder characterized by degeneration of motor neurons and weakness and muscle atrophy. Approximately 95% of SMA patients are caused by homozygous deletions of the SMN1 gene, whereas the remaining 5% of patients harbor compound heterozygous mutations such as an SMN1 deletion allele and an intragenic mutation (insertions, deletions, or point mutations) in the other SMN1 allele. Although analysis for the SMN1/SMN2 copy number is relatively easy, molecular genetic testing for patients with subtle mutations is still compromised due to the presence of a highly homologous SMN2 gene. Herein, we analyzed the SMN1/SMN2 copy number by multiplex ligation-dependent probe amplification (MLPA) and subtle mutations by long-range PCR (LR-PCR) for two "nondeletion" SMA patients. We identified a missense mutation (c.280G > T, p. (Val94Phe)) and a splicing mutation c.*3+3A > T in SMN1 gene not previously described in the scientific literature. Giving the severe phenotype of the two patients, we speculated that these two point mutations could significantly affect the function of SMN proteins. Our results provide important information for genetic counseling and prenatal diagnosis in these families and enrich the SMN1 mutation database.
脊髓性肌萎缩症（SMA）是一种常见的常染色体隐性遗传疾病，其特征是运动神经元变性和肌无力及肌肉萎缩。大约 95%的 SMA 患者是由 SMN1 基因的纯合缺失引起的，而其余 5%的患者则携带复合杂合突变，如 SMN1 缺失等位基因和另一个 SMN1 等位基因中的内含子突变（插入、缺失或点突变）。尽管 SMN1/SMN2 拷贝数的分析相对容易，但由于存在高度同源的 SMN2 基因，对于具有微妙突变的患者的分子遗传学检测仍然受到影响。在此，我们通过多重连接依赖性探针扩增（MLPA）分析了两个“非缺失”SMA 患者的 SMN1/SMN2 拷贝数，并通过长距离 PCR（LR-PCR）分析了微妙突变。我们在 SMN1 基因中发现了一个以前未在科学文献中描述过的错义突变（c.280G>T，p.（Val94Phe））和一个剪接突变 c.*3+3A>T。鉴于这两个患者的严重表型，我们推测这两个点突变可能会显著影响 SMN 蛋白的功能。我们的结果为这些家庭的遗传咨询和产前诊断提供了重要信息，并丰富了 SMN1 突变数据库。
