Huntington's disease (HD) is associated with the expansion of a CAG trinucleotide repeat in a novel gene. We have assessed 360 HD individuals from 259 unrelated families and found a highly significant correlation (r = 0.70, p = 10(-7)) between the age of onset and the repeat length, which accounts for approximately 50% of the variation in the age of onset. Significant associations were also found between repeat length and age of death and onset of other clinical features. Sib pair and parent-child analysis revealed that the CAG repeat demonstrates only mild instability. Affected HD siblings had significant correlations for trinucleotide expansion (r = 0.66, p < 0.001) which was not apparent for affected parent-child pairs.

Factors influencing the rate, form, and severity of phenotypic expression among relatives of autistic probands are examined. Family history data on 3095 first- and second-degree relatives and cousins from 149 families with a child with autism and 36 families with a child with Down syndrome are studied. The results provide further evidence of an increased risk among autism relatives for the broadly defined autism phenotype. Of proband characteristics, severity of autism and obstetric optimality were confirmed as being related to familial loading for probands with speech. There was little variation in loading among probands lacking speech. The type of phenotypic profile reported in relatives appeared little influenced by characteristics of the relative or the proband, except for variation by degree of relative, parental status of relative, and perhaps proband's birth optimality score. Phenotypic rates among parents suggested reduced fitness for the severest and more communication-related forms of expression but not for the more mild and social forms of expression. Patterns of expression within the families did not support a simple X-linked nor an imprinted X-linked mode of inheritance. The basis for sex differences in rates of expression is discussed.

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 investigate sequential events underlying HD. We show the existence of an intermediate 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 unstable and in the sporadic cases, expand to the full mutation associated with the phenotype of HD. This expansion has been shown to occur only during transmission through the male germline and is associated with advanced paternal age. These findings suggest that new mutations for 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.

We have analysed the CAG repeat in the Huntington disease (HD) gene in sperm and blood from 20 unrelated HD patients. Although the CAG repeat displayed significant mosaicism in sperm from all individuals, there were marked differences in the degree of repeat instability. Individuals who had either inherited or transmitted an expanded CAG repeat displayed the highest levels of repeat mosaicism, whereas individuals who had inherited or transmitted a contracted repeat had very limited CAG mosaicism in sperm. A strong association between intergenerational change in CAG allele size and the level of sperm repeat mosaicism was determined (P = 0.019). In contrast, neither blood CAG size nor repeat mosaicism in blood, were significantly associated with intergenerational CAG changes. These data suggest the presence of a cis-acting factor, separate from CAG size, that strongly influences the intergenerational behaviour of the CAG repeat. Additional studies are needed to determine whether analysis of CAG mosaicism in sperm is useful for assessing an individual's risk for transmitting large expansions or contractions to his offspring.

Parents of 144 children with autism spectrum disorders were surveyed regarding their perceptions of and satisfaction with the education their children were receiving. This article focuses on an analysis of the parents' responses to the open-ended questions of this survey. Overall themes that emerged repeatedly across all questions concerned the ability of school personnel to effectively manage children's behavior, teacher education and understanding of the disability, and effective communication and collaboration between parents and school. The implications for future research and practice emerging from these findings are discussed.