Genetic instability and hematologic disease risk in Werner syndrome patients and heterozygotes

Werner syndrome (WRN) is an uncommon autosomal recessive disease in which p rogeroid features are associated with genetic instability and an elevated r isk of neoplasia. We have used the glycophorin A (GPA) somatic cell mutatio n assay to analyze genetic instability in vivo in WRN patients acid heteroz ygotes. GPA variant frequencies were determined for 11 WRN patients and for 10 heterozygous family members who collectively carry 10 different WRN mut ations. Genetic instability as measured by GPA O/N allele loss variant freq uency was significantly increased, and this increase was strongly age-depen dent in WRN patients. CPA O/N allele loss variants were also significantly elevated in heterozygous family members, thus providing the first evidence for in vivo genetic instability in heterozygous carriers in an autosomal re cessive genetic instability syndrome. Our results and comparable data on ot her human genetic instability syndromes allow an estimate of the level of g enetic instability that increases the risk of human bone marrow dysfunction or neoplasia.