Human Molecular Genetics, Vol 6, 301-309, Copyright © 1997 by Oxford University Press
SS Chong, E Almqvist, H Telenius, L LaTray, K Nichol, B Bourdelat-Parks, YP Goldberg, BR Haddad, F Richards, D Sillence, CR Greenberg, E Ives, G Van den Engh, MR Hughes and MR Hayden
New mutations for Huntington disease (HD) arise from intermediate alleles
(IAs) with between 29 and 35 CAG repeats that expand on transmission
through the paternal germline to 36 CAGs or greater. Using single sperm
analysis, we have assessed CAG mutation frequencies for four IAs in
families with sporadic HD (IANM) and IAs ascertained from the general
population (IAGP) by analyzing 1161 single sperm from three persons. We
show that IANM are more unstable than IAGP with identical size and
sequence. Furthermore, comparison of different sized IAs and IAs with
different sequences between the CAG and the adjacent CCG tracts indicates
that DNA sequence is a major influence on CAG stability. These studies
provide estimates of the likelihood of expansion of IANM and IAGP to >
or = 36 CAG repeats for these individuals. For an IA with a CAG of 35 in
this family with sporadic HD, the likelihood for siblings to inherit a
recurrent mutation > or = 36 CAG is approximately 10%. For IAGP of a
similar size, the risk of inheriting an expanded allele of > or = 36 CAG
through the paternal germline is approximately 6%. These risk estimates are
higher than previously reported and provide additional information for
counselling in these families. Further studies on persons with IAs will be
needed to determine whether these results can be generalized to other
families.
ARTICLES
Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses
National Center for Human Genome Research, National Institutes of Health, Bethesda, MD 29892-4470, USA.
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