Yp. Goldberg et al., MOLECULAR ANALYSIS OF NEW MUTATIONS FOR HUNTINGTONS-DISEASE - INTERMEDIATE ALLELES AND SEX OF ORIGIN EFFECTS, Nature genetics, 5(2), 1993, pp. 174-179
Huntington's disease (HD) is associated with expansion of a CAG repeat
in a novel gene. We have assessed 21 sporadic cases of HD to investig
ate sequential events underlying HD. We show the existence of an inter
mediate allele (IA) in parental alleles of 30-38 CAG repeats in the HD
gene which is greater than usually seen in the general population but
below the range seen in patients with HD. These IAs are meiotically u
nstable and in the sporadic cases, expand to the full mutation associa
ted with the phenotype of HD. This expansion has been shown to occur o
nly during transmission through the male germline and is associated wi
th advanced paternal age. These findings suggest that new mutations fo
r HD are more frequent than prior estimates and indicate a previously
unrecognized risk of inheriting HD to siblings of sporadic cases of HD
and their children.