Hereditary spastic paraplegia is a group of rare motor neuron diseases considered to be inherited in a classical monogenic Mendelian manner. Although the typical inheritance of spastic paraplegia type 7 is autosomal recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant HSP. We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of hereditary spastic paraplegia patients and controls to examine the association of SPG7 and hereditary spastic paraplegia. In total, 585 hereditary spastic paraplegia patients from 372 families and 1,175 controls, including 580 unrelated individuals, were analyzed for the presence of SPG7 variants. Whole exome sequencing was performed on 400 hereditary spastic paraplegia patients (291 index cases) and all 1,175 controls. After excluding 38 biallelic hereditary spastic paraplegia type 7 patients, the frequency of heterozygous pathogenic/likely pathogenic SPG7 variant carriers (4.8%) among hereditary spastic paraplegia unrelated index cases who underwent WES, was significantly 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 cases vs. 0.85% in unrelated controls (OR=4.42, 95%CI=1.49-13.07, p=0.005). We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in genes known to cause hereditary spastic paraplegia, compared to zero in controls (OR=19.58, 95%CI=1.05-365.13, p=0.0031; Fisher Exact test with Haldane-Anscombe correction), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2 and MORC2). Out 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 hereditary spastic paraplegia, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance.

中文翻译：

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痉挛性截瘫的非孟德尔遗传证据7

遗传性痉挛性截瘫是一组罕见的运动神经元疾病，被认为以经典的单基因孟德尔方式遗传。尽管痉挛性截瘫的典型遗传是7型常染色体隐性遗传，但有一些报道表明SPG7变异也可能导致常染色体显性HSP。我们旨在对遗传性痉挛性截瘫患者和对照的加拿大大型队列进行全基因组遗传分析，以检查SPG7与遗传性痉挛性截瘫的关系。总共分析了来自372个家庭和1175个对照组（包括580个无关个体）的585名遗传性痉挛性截瘫患者的SPG7变异体的存在。对400名遗传性痉挛性截瘫患者（291名索引病例）和所有1,175名对照进行了完整的外显子组测序。在排除38名双等位遗传性痉挛性截瘫7型患者之后，接受WES的遗传性痉挛性截瘫无关指数病例中杂合的病原性/可能致病性SPG7变异携带者的频率（4.8％）显着高于无关对照（1.7％; OR = 2.88，95％CI = 1.24-6.66，p = 0.009）。在3.7％的索引病例中发现了杂合的SPG7 p。（Ala510Val）变体，而在不相关的对照中则为0.85％（OR = 4.42，95％CI = 1.49-13.07，p = 0.005）。我们在已知会导致遗传性痉挛性截瘫的基因中鉴定出四种杂合的SPG7变异携带者，以及其他致病变异，而在对照中则为零（OR = 19.58，95％CI = 1.05-365.13，p = 0.0031；采用Haldane-Anscombe进行Fisher精确检验校正），表明潜在的双基因遗传。我们进一步确定了在SPG7和SPG7相互作用基因（CACNA1A，AFG3L2和MORC2）中具有杂合变异体的四个家族。其中，特别令人信服的证据表明SPG7与AFG3L2之间存在上皮转移。AFG3L2中的p。（Ile705Thr）变体位于六聚体亚基之间的界面，处于与脊髓小脑共济失调类型28相关的影响其蛋白水解功能的突变热点。我们的结果为SPG7相关的遗传性痉挛性截瘫的复杂遗传提供了证据，其中可能包括隐性遗传，也可能包括显性遗传和双基因/脓毒症遗传。AFG3L2中的（Ile705Thr）变体位于六聚体亚基之间的界面，处于与脊髓小脑共济失调类型28相关的影响其蛋白水解功能的突变热点。我们的结果为SPG7相关的遗传性痉挛性截瘫的复杂遗传提供了证据，其中可能包括隐性遗传，也可能包括显性遗传和双基因/脓毒症遗传。AFG3L2中的（Ile705Thr）变体位于六聚体亚基之间的界面，处于与脊髓小脑共济失调类型28相关的影响其蛋白水解功能的突变热点。我们的结果为SPG7相关的遗传性痉挛性截瘫的复杂遗传提供了证据，其中可能包括隐性遗传，也可能包括显性遗传和双基因/脓毒症遗传。