RT Journal Article
SR Electronic
T1 Evidence for genetic anticipation in von Hippel-Lindau syndrome
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP jmedgenet-2017-104882
DO 10.1136/jmedgenet-2017-104882
A1 Laura Aronoff
A1 David Malkin
A1 Kalene van Engelen
A1 Bailey Gallinger
A1 Jonathan Wasserman
A1 Raymond H Kim
A1 Anita Villani
A1 M Stephen Meyn
A1 Harriet Druker
YR 2018
UL http://jmg.bmj.com/content/early/2018/02/06/jmedgenet-2017-104882.abstract
AB Background 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.Methods 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 VHL pathogenic variant carriers.Results 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=6.00×10-12). 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.Conclusions 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.