Molecular analysis of juvenile Huntington disease: the major influence on (CAG)_n repeat length is the sex of the affected parent

Abstract

Juvenile Huntington disease (HD), characterised by onset of symptoms before the age of 20 with rigidity and intellectual decline, is associated with a predominance of affected fathers. In order to investigate the molecular basis for the observed parental effect, we have analysed the CAG trinucleotide repeat within the HD gene in 42 juvenile onset cases from 34 families. A highly significant correlation was found between the repeat length and age of onset (r = -0.86, p < 10(-7) and it was determined that the sex of transmitting parent was the major influence on CAG expansion leading to earlier onset. Neither the size of the parental upper allele, the age of parent at conception of juvenile onset child, nor the grandparental sex conferred a significant effect upon expansion. Affected sib pair analysis of CAG repeat length, however, revealed a high correlation (r = 0.91, p < 10(-7). Furthermore, analysis of nuclear and extended families showed a familial predisposition to juvenile onset disease. This study demonstrates that the sex of transmitting parent is the major influence on trinucleotide expansion and clinical features in juvenile Huntington disease.

Somatic mosaicism in sperm is associated with intergenerational (CAG)n changes in Huntington disease

“…In contrast, maternal age did not influence anticipation (36). It has been shown subsequently that anticipation is closely correlated with an expansion o f the CAG repeat, and in cases o f very large expansions results in juvenile onset (16). Taken together, these data would appear to suggest that older fathers are more likely to transmit further expanded CAG repeats, with anticipation in the affected offspring.…”

“…Age of onset is inversely correlated with the CAG repeat length, such that a longer repeat in a patient is associated with a younger age of onset (8)(9)(10)(11)(12)(13)(14)(15). Analysis of 42 juvenile onset probands revealed that the anticipation observed in these families is closely correlated with an intergenerational expansion of the repeat, from the adult onset parent to the juvenile onset child (16). The largest expansions occurred exclusively via male transmission, providing an explanation for the previously recognised predominance of affected fathers of patients with juvenile onset disease (1,2,17).…”

“…The familial aggregation of expansions or reversions in specific families, including the clustering of juvenile and late *To whom correspondence should be addressed onset in sibships, suggest that specific HD chromosomes are associated with particular levels o f CAG repeat instability (16,20). To exam ine this hypothesis at the molecular level, we have analysed sperm from 20 unrelated persons with CAG expansion in the HD gene.…”

Juvenile onset Huntington disease resulting from a very large maternal expansion

“…Earlier onset in successive generations within a pedigree or anticipation in HD has predominantly been reported to originate from paternal transmission through unknown mechanism(s) [Telenius et al, 1993;Trottier et al, 1994]. Juvenileonset HD before the age of 20 years occurs in about 5% of HD cases [Potter et al, 2004], and is associated with very large ( 60) CAG repeat expansions [Nance and Myers, 2001].…”

“…Cannella et al [2004] report a mean intergenerational expansion of þ7.3 repeats with paternal transmission and þ0.7 repeats with maternal transmission. In addition to parental sex, the size of parental CAG repeats influences the extent of intergenerational expansion [Telenius et al, 1993Kremer et al, 1995;Leeflang et al, 1995]. The largest reported intergenerational expansion is þ160 repeats wherein a father with 54 repeats had a child with 214 repeats [Seneca et al, 2004].…”