Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
J Med Genet. 2018 Jun;55(6):395-402. doi: 10.1136/jmedgenet-2017-104882. Epub 2018 Feb 7.
von Hippel-Lindau (vHL) syndrome is a rare autosomal-dominant disorder that confers a lifelong risk for developing both benign and malignant tumours in multiple organs. Recent evidence suggests that vHL may exhibit genetic anticipation (GA). The aim of this study was to determine if GA occurs in vHL, and if telomere shortening may be a factor in GA.
A retrospective chart review of vHL families seen at The Hospital for Sick Children between 1984 and 2016 was performed. Age of onset (AOO, defined as the age of first physician-diagnosed vHL-related manifestation) was confirmed for 96 patients from 20 unrelated families (80 clinically affected and 16 unaffected carriers). Flow-FISH(flow cytometry sorting of cells whose telomeres are labeled by Fluorescence In Situ Hybridization) was used to measure mean telomere length of six white blood cell subtypes from 14 known pathogenic variant carriers.
The median AOO for generations I, II and III were 32.5, 22.5 and 12.0 years, respectively. The differences in the AOO between generations were highly significant using a Cox proportional hazards model (P=6.00×10). Telomere lengths were significantly different for granulocytes and natural killer lymphocytes of patients with vHL compared with age-matched controls. For six vHL parent-child pairs, median white blood cell telomere lengths between parent and child were not significantly different.
Our results suggest that vHL telomere abnormalities may be primarily somatic in origin rather than a cause of GA. As tumour development exhibits GA in our cohort, vHL surveillance guidelines may need to account for a patient's generational position within a vHL pedigree.
von Hippel-Lindau（vHL）综合征是一种罕见的常染色体显性遗传病，终生存在多器官良性和恶性肿瘤的风险。最近的证据表明，vHL 可能存在遗传预期（GA）。本研究旨在确定 vHL 是否存在 GA，端粒缩短是否是 GA 的一个因素。
对 1984 年至 2016 年在 SickKids 医院就诊的 vHL 家族进行了回顾性图表审查。从 20 个无关家庭中确定了 96 名患者的发病年龄（AOO，定义为首次由医生诊断的与 vHL 相关表现的年龄）（80 例临床受累和 16 例无病携带者）。使用流式-FISH（通过荧光原位杂交标记细胞端粒的流式细胞分选）测量了 14 名已知致病性变异携带者的六种白细胞亚型的平均端粒长度。
第一代、第二代和第三代的中位 AOO 分别为 32.5、22.5 和 12.0 岁。Cox 比例风险模型显示，各代之间 AOO 的差异具有高度显著性（P=6.00×10）。与年龄匹配的对照组相比，vHL 患者的粒细胞和自然杀伤淋巴细胞的端粒长度明显不同。对于六个 vHL 父母-子女对，父母和子女之间的白细胞端粒长度中位数没有显著差异。
我们的结果表明，vHL 端粒异常可能主要是体细胞起源，而不是 GA 的原因。由于在我们的队列中肿瘤发展存在 GA，vHL 监测指南可能需要考虑患者在 vHL 家系中的代际位置。
