Goldman Jill S, Vallabh Sonia M
Columbia University Irving Medical Center, New York, NY.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA; Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Prion Alliance, Cambridge, MA.
Genet Med. 2022 Oct;24(10):1993-2003. doi: 10.1016/j.gim.2022.06.003. Epub 2022 Jul 12.
Prion disease is a rare, fatal, and often rapidly progressive neurodegenerative disease. Ten to fifteen percent of cases are caused by autosomal dominant gain-of-function variants in the prion protein gene, PRNP. Rarity and phenotypic variability complicate diagnosis, often obscuring family history and leaving families unprepared for the genetic implications of an index case. Several recent developments inspire this update in best practices for prion disease genetic counseling. A new prion-detection assay has transformed symptomatic diagnosis. Meanwhile, penetrance, age of onset, and duration of illness have been systematically characterized across PRNP variants in a global cohort. Clinically, the traditional genotype-phenotype correlation has weakened over time, and the term genetic prion disease may now better serve providers than the historical subtypes Creutzfeldt-Jakob disease, fatal familial insomnia, and Gerstmann-Sträussler-Scheinker disease. Finally, in the age of genetically targeted therapies, clinical trials for prion disease are being envisaged, and healthy at-risk individuals may be best positioned to benefit. Such individuals need to be able to access clinical services for genetic counseling and testing. Thus, this update on the genetics of prion disease and best practices for genetic counseling for this disease aims to provide the information needed to expand genetic counseling services.
朊病毒病是一种罕见、致命且通常进展迅速的神经退行性疾病。10%至15%的病例由朊病毒蛋白基因（PRNP）中的常染色体显性功能获得性变异引起。该病的罕见性和表型变异性使诊断变得复杂，常常模糊家族病史，让家庭对索引病例的遗传影响毫无准备。最近的几项进展促使了对朊病毒病遗传咨询最佳实践的更新。一种新的朊病毒检测方法改变了症状性诊断。与此同时，在一个全球队列中，已系统地描述了PRNP变异的外显率、发病年龄和病程。临床上，传统的基因型-表型相关性随着时间推移而减弱，与历史上的克雅氏病、致死性家族性失眠症和格斯特曼-施特劳斯勒-谢克尔病等亚型相比，“遗传朊病毒病”这一术语现在可能更有助于医护人员。最后，在基因靶向治疗的时代，正在设想针对朊病毒病的临床试验，健康的高危个体可能最有机会从中受益。这类个体需要能够获得遗传咨询和检测的临床服务。因此，本次关于朊病毒病遗传学及该病遗传咨询最佳实践的更新旨在提供扩大遗传咨询服务所需的信息。
