Abstract

Data from the US National Huntington's Disease Roster have been analysed in terms of the difference in age of onset (AO) between affected parents and affected offspring, that is, in terms of 'anticipation'. While mean AO in offspring of affected mothers did not differ greatly from AO in their mothers, the distribution of AO in the offspring of affected fathers falls into two groups, the larger group showing an AO only slightly younger than their affected fathers and a small group whose AO was, on average, 24 years younger than their affected fathers. Analysis of the grandparental origin of the Huntington allele suggests that while propensity to anticipation is heritable for a number of generations through the male line, it originates at the time of differentiation of the germ line of a male who acquires the Huntington allele from his mother. It is suggested that major anticipation indicates an epigenetic change in methylation of the nucleic acid of the genome, which is imposed in the course of the 'genomic imprinting', that is, in the mechanism by which the parental origin of alleles is indicated.