The G₄C₂-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10⁻⁵). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

中文翻译：

---

SLITRK2，C9orf72 额颞叶变性发病年龄的 X 连锁修饰符

C9orf72中的G ₄ C ₂重复扩增是额颞叶痴呆和肌萎缩侧索硬化的最常见原因。发病年龄和表型表现的可变性是C9orf72疾病的标志。在这项研究中，我们旨在使用基于家庭的方法，在成对的发病年龄一致或不一致的C9orf72携带者亲属中确定C9orf72携带者疾病发作的修饰因素。连锁和关联分析为染色体 Xq27.3 上的一个基因座提供了聚合证据。rs1009776 的次要等位基因 A 与较早发作有关 ( P  = 1 × 10 ^-5). 在无关的C9orf72患者的独立队列中复制了与痴呆发作的关联( P  = 0.009)。根据所考虑的队列，保护性主要等位基因将痴呆症的发作平均延迟 5 至 13 年。在C9orf72患者的独立队列中观察到相同的趋势，发病年龄存在极大偏差 ( P  = 0.055)。在GRN患者中未检测到 rs1009776 的关联，这表明 rs1009776 的作用仅限于C9orf72引起的痴呆发作。次要等位基因 A 与更高的SLITRK2相关基于表达数量性状位点 (eQTL) 数据库和对C9orf72脑组织进行的内部表达研究的表达。SLITRK2编码突触后粘附蛋白。我们进一步表明，突触小泡糖蛋白 2 和突触素这两种突触小泡蛋白在携带次要等位基因的C9orf72患者的额叶皮质中减少。SLITRK2的上调可能与突触功能障碍有关，并在C9orf72患者中引发不良反应，这些不良反应可在携带保护性等位基因的患者中进行调节。SLITRK2表达的调节如何影响突触功能并影响痴呆症的发病C9orf72载体将需要进一步调查。总之，这项研究描述了一种检测罕见疾病修饰基因的原始方法，并加强了C9orf72与可能直接影响首发症状发生的突触功能障碍之间不断上升的联系。