Jump from Pre-mutation to Pathologic Expansion in XXXX .

@entity1 @entity747 @entity3301 @entity746
UNASSIGNED: An expanded G4C2 repeat in @entity3301 represents the most common known genetic cause of @entity746 ( @entity746 ) and @entity747 ( @entity747 ). However, the lower limit for pathological expansions is unknown (the suggested cutoff is 30 repeats). It has been proposed that the expansion might have occurred only once in @entity1 history and subsequently spread throughout the population. However, our present findings support a hypothesis of multiple origins for the expansion. We report a British-Canadian family in whom a    70-repeat allele from the father (unaffected by @entity746 or @entity747 at age 89 years) expanded during parent-offspring transmission and started the first generation affected by @entity746 (four @entity1 carry an    1,750-repeat allele). Epigenetic and RNA-expression analyses further discriminated the offspring's large expansions (which were methylated and associated with reduced @entity3301 expression) from the    70-repeat allele (which was unmethylated and associated with upregulation of @entity3301 ). Moreover, RNA foci were only detected in fibroblasts from offspring with large expansions, but not in the father, who has the    70-repeat allele. All family members with expansions were found to have an ancient known risk haplotype, although it was inherited on a unique 5-Mb genetic backbone. We conclude that small expansions (e.g., 70 repeats) might be considered "pre-mutations" to reflect their propensity to expand in the next generation. Follow-up studies might help explain the high frequency of @entity746 - or @entity747 -affected individuals with an expansion but without a familial history (e.g., 21% among Finnish @entity746 subjects).
