Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
Department of Clinical Genetics, Medirex A.S., Kosice, Slovakia.
Mol Genet Genomic Med. 2020 Jul;8(7):e1238. doi: 10.1002/mgg3.1238. Epub 2020 Apr 26.
Spinal muscular atrophy (SMA) is an inherited neuromuscular disease affecting 1 in 8,000 newborns. The majority of patients carry bi-allelic variants in the survival of motor neuron 1 gene (SMN1). SMN1 is located in a duplicated region on chromosome 5q13 that contains Alu elements and is predisposed to genomic rearrangements. Due to the genomic complexity of the SMN region and genetic heterogeneity, approximately 50% of SMA patients remain without genetic diagnosis that is a prerequisite for genetic treatments. In this work we describe the diagnostic odyssey of one SMA patient in whom routine diagnostics identified only a maternal heterozygous SMN1Δ(7-8) deletion.
We characterized SMN transcripts, assessed SMN protein content in peripheral blood mononuclear cells (PBMC), estimated SMN genes dosage, and mapped genomic rearrangement in the SMN region.
We identified an Alu-mediated deletion encompassing exons 2a-5 of SMN1 on the paternal allele and a complete deletion of SMN1 on the maternal allele as the cause of SMA in this patient.
Alu-mediated rearrangements in SMN1 can escape routine diagnostic testing. Parallel analysis of SMN gene dosage, SMN transcripts, and total SMN protein levels in PBMC can identify genomic rearrangements and should be considered in genetically undefined SMA cases.
脊髓性肌萎缩症（SMA）是一种遗传性神经肌肉疾病，影响每 8000 名新生儿中的 1 名。大多数患者携带运动神经元生存基因 1 号（SMN1）的双等位基因变异。SMN1 位于染色体 5q13 的重复区域，其中包含 Alu 元件，易发生基因组重排。由于 SMN 区域的基因组复杂性和遗传异质性，约 50%的 SMA 患者仍未进行遗传诊断，这是遗传治疗的前提。在这项工作中，我们描述了一位 SMA 患者的诊断历程，常规诊断仅确定了母亲杂合的 SMN1Δ(7-8)缺失。
我们对 SMN 转录本进行了特征分析，评估了外周血单核细胞（PBMC）中的 SMN 蛋白含量，估计了 SMN 基因的剂量，并对 SMN 区域的基因组重排进行了定位。
我们发现该患者的 SMA 是由父本等位基因上的 Alu 介导的包含 SMN1 外显子 2a-5 的缺失和母本等位基因上的 SMN1 完全缺失引起的。
Alu 介导的 SMN1 重排可能逃避常规诊断测试。在 PBMC 中平行分析 SMN 基因剂量、SMN 转录本和总 SMN 蛋白水平可以识别基因组重排，并且应该在遗传上未定义的 SMA 病例中考虑。
