PDF(Pubmed)
Abstract：
BACKGROUND: Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11 gene (MIM *610844).
METHODS: The proband is a 36-year-old female referred for genetic evaluation due to cognitive dysfunction, gait impairment, and corpus callosum atrophy (brain MRI was normal at 25-years-old). Diagnostic approaches included CGH array, next-generation sequencing, and whole transcriptome sequencing.
RESULTS: CGH array revealed a 180 kb deletion located upstream of SPG11. Sequencing of SPG11 uncovered two rare single nucleotide variants: the novel variant c.3143C>T in exon 17 (in cis with the deletion), and the previously reported pathogenic variant c.6409C>T in exon 34 (in trans). Whole transcriptome sequencing revealed that the variant c.3143C>T caused exon 17 skipping.
CONCLUSIONS: We report a novel sequence variant in the SPG11 gene resulting in exon 17 skipping, which, along with a nonsense variant, causes Spastic Paraplegia 11 in our proband. In addition, a deletion upstream of SPG11 was identified in the patient, whose implication in the phenotype remains uncertain. Nonetheless, the deletion apparently affects cis-regulatory elements of the gene, suggesting a potential new pathogenic mechanism underlying the disease in a subset of undiagnosed patients. Our findings further support the hypothesis that the origin of thin corpus callosum in patients with SPG11 is of progressive nature.
METHODS: The proband is a 36-year-old female referred for genetic evaluation due to cognitive dysfunction, gait impairment, and corpus callosum atrophy (brain MRI was normal at 25-years-old). Diagnostic approaches included CGH array, next-generation sequencing, and whole transcriptome sequencing.
RESULTS: CGH array revealed a 180 kb deletion located upstream of SPG11. Sequencing of SPG11 uncovered two rare single nucleotide variants: the novel variant c.3143C>T in exon 17 (in cis with the deletion), and the previously reported pathogenic variant c.6409C>T in exon 34 (in trans). Whole transcriptome sequencing revealed that the variant c.3143C>T caused exon 17 skipping.
CONCLUSIONS: We report a novel sequence variant in the SPG11 gene resulting in exon 17 skipping, which, along with a nonsense variant, causes Spastic Paraplegia 11 in our proband. In addition, a deletion upstream of SPG11 was identified in the patient, whose implication in the phenotype remains uncertain. Nonetheless, the deletion apparently affects cis-regulatory elements of the gene, suggesting a potential new pathogenic mechanism underlying the disease in a subset of undiagnosed patients. Our findings further support the hypothesis that the origin of thin corpus callosum in patients with SPG11 is of progressive nature.
摘要：
背景：痉挛性截瘫11（SPG11）是常染色体隐性遗传性痉挛性截瘫的最普遍形式，由SPG11基因(MIM*610844)的双等位基因致病变异产生。
方法：先证者是一名36岁女性，因认知功能障碍而接受基因评估，步态障碍,和call体萎缩（25岁时脑MRI正常）。诊断方法包括CGH阵列，下一代测序，和整个转录组测序。
结果：CGH阵列显示位于SPG11上游的180kb缺失。SPG11的测序揭示了两个罕见的单核苷酸变体：外显子17中的新变体c.3143C>T（顺式缺失），和先前报道的致病变异c.6409C>T在外显子34（反式）。全转录组测序显示变异c.3143C>T引起外显子17跳跃。
结论：我们报告了SPG11基因中的一个新的序列变异，导致外显子17跳跃，which,连同一个无稽之谈的变体，在我们的先证者中导致痉挛性截瘫11。此外,在患者中发现了SPG11上游的缺失，其在表型中的含义仍不确定。尽管如此，缺失显然会影响基因的顺式调节元件，提示在一部分未确诊的患者中潜在的新致病机制。我们的发现进一步支持以下假设：SPG11患者的瘦call体的起源具有进行性。
方法：先证者是一名36岁女性，因认知功能障碍而接受基因评估，步态障碍,和call体萎缩（25岁时脑MRI正常）。诊断方法包括CGH阵列，下一代测序，和整个转录组测序。
结果：CGH阵列显示位于SPG11上游的180kb缺失。SPG11的测序揭示了两个罕见的单核苷酸变体：外显子17中的新变体c.3143C>T（顺式缺失），和先前报道的致病变异c.6409C>T在外显子34（反式）。全转录组测序显示变异c.3143C>T引起外显子17跳跃。
结论：我们报告了SPG11基因中的一个新的序列变异，导致外显子17跳跃，which,连同一个无稽之谈的变体，在我们的先证者中导致痉挛性截瘫11。此外,在患者中发现了SPG11上游的缺失，其在表型中的含义仍不确定。尽管如此，缺失显然会影响基因的顺式调节元件，提示在一部分未确诊的患者中潜在的新致病机制。我们的发现进一步支持以下假设：SPG11患者的瘦call体的起源具有进行性。
