Lian Yuan, Kotobelli Keisi, Hall Stacey, Talkowski Michael E, O'Donnell-Luria Anne, Vallabh Sonia M, Appleby Brian S, Minikel Eric Vallabh
Program in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, 44106, USA.
medRxiv. 2025 Mar 17:2024.12.12.24318867. doi: 10.1101/2024.12.12.24318867.
Variably protease-sensitive prionopathy (VPSPr) is a rare, atypical subtype of prion disease currently classified as sporadic. We performed exome sequencing and targeted sequencing of non-coding regions on genomic DNA from autopsy-confirmed VPSPr patients (N=67) in order to search for a possible genetic cause. Our search identified no potentially causal variants for VPSPr. The common polymorphism M129V was the largest genetic risk factor for VPSPr, with an odds ratio of 7.0. Other variants in and near exhibited association to VPSPr risk only in proportion to their linkage disequilibrium with M129V, and upstream expression quantitative trait loci showed no evidence of independent association to VPSPr risk. We cannot rule out the possibility of causal variants hiding in genomic regions or classes of genetic variation that our search did not canvas. Nevertheless, our data support the classification of VPSPr as a sporadic prion disease.
可变蛋白酶敏感性朊病毒病（VPSPr）是一种罕见的、非典型的朊病毒病亚型，目前归类为散发性疾病。我们对尸检确诊的VPSPr患者（N = 67）的基因组DNA进行了外显子组测序和非编码区靶向测序，以寻找可能的遗传病因。我们的搜索未发现VPSPr的潜在致病变异。常见的多态性M129V是VPSPr最大的遗传风险因素，优势比为7.0。其他基因内和附近的变异仅与其与M129V的连锁不平衡程度相关，与VPSPr风险相关，并且上游表达数量性状位点没有显示出与VPSPr风险独立相关的证据。我们不能排除致病变异隐藏在我们的搜索未涵盖的基因组区域或遗传变异类型中的可能性。然而，我们的数据支持将VPSPr归类为散发性朊病毒病。
