Department of Human Genetics, McGill University, Montréal, Québec, Canada.
The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Québec, Canada.
Mov Disord. 2021 Jul;36(7):1664-1675. doi: 10.1002/mds.28528. Epub 2021 Feb 17.
Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP).
We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of SPG7 and HSP.
We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals. Whole-exome sequencing was performed on 400 HSP patients (291 index cases) and all 1175 controls.
The frequency of heterozygous pathogenic/likely pathogenic SPG7 variants (4.8%) among unrelated HSP patients was higher than among unrelated controls (1.7%; OR 2.88, 95% CI 1.24-6.66, P = 0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index patients versus 0.85% in unrelated controls (OR 4.42, 95% CI 1.49-13.07, P = 0.005). Similar results were obtained after including only genetically-undiagnosed patients. We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, compared to zero in controls (OR 19.58, 95% CI 1.05-365.13, P = 0.0031), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2). Of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function.
Our results provide evidence for complex inheritance in SPG7-associated HSP, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance. © 2021 International Parkinson and Movement Disorder Society.
虽然痉挛性截瘫 7 型的典型遗传方式为隐性遗传，但有几项报告表明 SPG7 变异也可能导致常染色体显性遗传性痉挛性截瘫（HSP）。
我们旨在对一个大型加拿大 HSP 患者和对照者队列进行外显子组全基因组遗传分析，以研究 SPG7 与 HSP 的关联。
我们分析了 372 个家系的 585 名 HSP 患者和 1175 名对照者，包括 580 名无关个体。对 400 名 HSP 患者（291 名索引病例）和所有 1175 名对照者进行了全外显子组测序。
在无关 HSP 患者中，杂合致病性/可能致病性 SPG7 变异的频率（4.8%）高于无关对照者（1.7%；OR 2.88，95%CI 1.24-6.66，P=0.009）。索引患者中发现杂合 SPG7 p.（Ala510Val）变异的频率为 3.7%，而无关对照者为 0.85%（OR 4.42，95%CI 1.49-13.07，P=0.005）。仅纳入遗传上未确诊的患者后，得到了相似的结果。与对照者相比，我们在 4 名杂合 SPG7 变异携带者中发现了另外一个已知 HSP 基因中的致病性变异，而对照者中没有（OR 19.58，95%CI 1.05-365.13，P=0.0031），提示可能存在双基因遗传。我们进一步鉴定了 4 个携带 SPG7 和 SPG7 相互作用基因（CACNA1A、AFG3L2 和 MORC2）杂合变异的家系。其中，SPG7 与 AFG3L2 之间存在明显的上位性效应。AFG3L2 中的 p.（Ile705Thr）变异位于六聚体亚基的界面处，是与脊髓小脑共济失调 28 型相关的突变热点，影响其蛋白水解功能。
我们的结果为 SPG7 相关 HSP 的复杂遗传提供了证据，这可能包括隐性遗传，以及可能的显性遗传和双基因/上位性遗传形式。
