Hôpital Neurologique Pierre Wertheimer, Service d'électroneuromyographie et de Pathologies Neuromusculaires, Hospices Civils de Lyon, Groupement Est, Bron, France.
Pathophysiology and Genetics of Neuron and Muscle, CNRS UMR 5261, INSERM U1315, Université Lyon1, Faculté de Médecine Lyon Est, Lyon, France.
Eur J Hum Genet. 2024 Jan;32(1):37-43. doi: 10.1038/s41431-023-01407-8. Epub 2023 Jun 19.
Proximal spinal muscular atrophy (SMA) is defined by a degeneration of the anterior horn cells resulting in muscle weakness predominantly in the proximal lower limbs. While most patients carry a biallelic deletion in the SMN1 gene (localized in chromosome 5q), little is known regarding patients without SMN1-mutation, and a genetic diagnosis is not always possible. Here, we report a cohort of 24 French patients with non-5q proximal SMA from five neuromuscular centers who all, except two, had next-generation sequencing (NGS) gene panel, followed by whole exome sequencing (WES) if gene panel showed a negative result. The two remaining patients benefited directly from WES or whole genome sequencing (WGS). A total of ten patients with causative variants were identified, nine of whom were index cases (9/23 families = 39%). Eight variants were identified by gene panel: five variants in DYNC1H1, and three in BICD2. Compound heterozygous causative variants in ASAH1 were identified directly by WES, and one variant in DYNC1H1 was identified directly by WGS. No causative variant was found using WES in patients with a previous panel with negative results (14 cases). We thus recommend using primarily NGS panels in patients with non-5q-SMA and using WES, especially when several members of the same family are affected and/or when trio analyses are possible, or WGS as second-line testing if available.
近端型脊肌萎缩症（SMA）是由于前角细胞变性导致的肌肉无力，主要影响近端下肢。大多数患者在 SMN1 基因（位于 5q 染色体上）中存在双等位基因缺失，但对于无 SMN1 突变的患者知之甚少，且并非总能进行基因诊断。本研究报告了来自五个神经肌肉中心的 24 例法国非 5q 近端型 SMA 患者，除了两名患者外，其余患者均进行了下一代测序（NGS）基因 panel 检测，如果基因 panel 结果为阴性，则进一步进行全外显子测序（WES）。另外两名患者直接受益于 WES 或全基因组测序（WGS）。共发现 10 例有致病变异的患者，其中 9 例为首发患者（9/23 个家系=39%）。8 个变异通过基因 panel 发现：5 个变异位于 DYNC1H1 中，3 个变异位于 BICD2 中。通过 WES 直接发现 ASAH1 的复合杂合致病变异，通过 WGS 直接发现 DYNC1H1 的一个变异。在先前 panel 结果为阴性的 14 例患者中，通过 WES 未发现致病变异。因此，我们建议在非 5q-SMA 患者中主要使用 NGS panel，并在有多个家族成员受累和/或可进行 trio 分析时使用 WES，或者在有条件时使用 WGS 作为二线检测。
