Factors associated with HD CAG repeat instability in Huntington disease

Wheeler, Vanessa C.; Persichetti, Francesca; McNeil, Sandra; Mysore, Jayalakshmi Srinidhi; Mysore, S S; MacDonald, Marcy E.; Myers, Richard H.; Gusella, James F.; Wexler, Nancy S.

doi:10.1136/jmg.2007.050930

Cited by 116 publications

(113 citation statements)

References 30 publications

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“…In our study, the maternal transmission of longer expanded alleles was more frequently observed in sons than in daughters. These results are similar to that reported by Wheeler et al 31 We found that a greater variation in number of CAG occurred when the HD allele was paternally transmitted, and the only repeat contraction occurred when the mutation was maternally transmitted to a son. Wheeler et al 31 observed a greater number of repeat contractions when the allele was transmitted from mothers to daughters.…”

Section: Discussionsupporting

confidence: 92%

“…In our survey, the mean size of the paternally inherited CAG alleles was 42.25±2.6 repeats. A similar result was found in the Venezuelan kindred study, 31 which showed a mean value of 44.4 CAG repeats.…”

Section: Discussionsupporting

confidence: 87%

“…This change is higher than that found in a previous study conducted in Venezuela, where the mean intergenerational change was 1.27 repeats. 31 However, these two estimates are not significantly different because of the relatively large standard deviations. In our survey, the mean size of the paternally inherited CAG alleles was 42.25±2.6 repeats.…”

Section: Discussionmentioning

confidence: 94%

“…The variability in the size of the transmitted CAG repeats was also investigated by Wheeler et al 31 in Venezuela relative to the gender of the siblings. In our study, the maternal transmission of longer expanded alleles was more frequently observed in sons than in daughters.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies, 31,32 which looked at additional expansion of CAG repeats within a generation (intergenerational studies), showed that there is a significant difference between the maternal and paternal inheritance of alleles with large CAG repeat expansions (Po0.0001). Specifically, they found that fathers transmit longer expanded alleles more often than mothers do.…”

Section: Discussionmentioning

confidence: 99%

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Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease

et al. 2012

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We studied the allelic profile of CAG and CCG repeats in 61 Brazilian individuals in 21 independent families affected by Huntington's disease (HD). Thirteen individuals had two normal alleles for HD, two had one mutable normal allele and no HD phenotype, and forty-six patients carried at least one expanded CAG repeat allele. Forty-five of these individuals had one expanded allele and one individual had one mutable normal allele (27 CAG repeats) and one expanded allele (48 CAG repeats). Eleven of these forty-five subjects had a mutant allele with reduced penetrance, and thirty-four patients had a mutant allele with complete penetrance. Inter-and intragenerational investigations of CAG repeats were also performed. We found a negative correlation between the number of CAG repeats and the age of disease onset (r ¼ À0.84; Po0.001) and no correlation between the number of CCG repeats and the age of disease onset (r ¼ 0.06). We found 40 different haplotypes and the analysis showed that (CCG) 10 was linked to a CAG normal allele in 19 haplotypes and to expanded alleles in two haplotypes. We found that (CCG) 7 was linked to expanded CAG repeats in 40 haplotypes (95.24%) and (CCG) 10 was linked to expanded CAG repeats in only two haplotypes (4.76%). Therefore, (CCG) 7 was the most common allele in HD chromosomes in this Brazilian sample. It was also observed that there was a significant association of (CCG) 7 with the expanded CAG alleles (v 2 ¼ 6.97, P ¼ 0.0084). Worldwide, the most common CCG alleles have 7 or 10 repeats. In Western Europe, (CCG) 7 is the most frequent allele, similarly to our findings.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease

et al. 2012

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Common Premutations in the General Population

Hammer

Singleton

2019

JAMA Neurol

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Prevalence of Carriers of Intermediate and Pathological Polyglutamine Disease–Associated Alleles Among Large Population-Based Cohorts

et al. 2019

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IMPORTANCE Nine hereditary neurodegenerative diseases are known as polyglutamine diseases, including Huntington disease, 6 spinocerebellar ataxias (SCAs) (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17), dentatorubral-pallidoluysion atrophy, and spinal bulbar muscular atrophy. OBJECTIVE To determine the prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among the general population. DESIGN, SETTING, AND PARTICIPANTS This observational cross-sectional study included data from 5 large European population-based cohorts that were compiled between 1997 and 2012, and the analyses were conducted in 2018. In total, 16 547 DNA samples were obtained from participants of the 5 cohorts. Individuals with a lifetime diagnosis of major depression were excluded (n = 2351). In the remaining 14 196 participants without an established polyglutamine disease diagnosis, the CAG repeat size in both alleles of all 9 polyglutamine disease-associated genes (PDAGs) (ie, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1, and AR) was determined. EXPOSURE The number of CAG repeats in the alleles of the 9 PDAGs. MAIN OUTCOMES AND MEASURES The number of individuals with alleles within the intermediate or pathological range per PDAG, as well as differences in sex, age, and body mass index between individuals carrying alleles within the normal or intermediate range and individuals carrying alleles within the pathological range of PDAGs. RESULTS In the 14 196 analyzed participants (age range, 18-99 years; 56.3% female), 10.7% had a CAG repeat number within the intermediate range of at least 1 PDAG. Moreover, up to 1.3% of the participants had a CAG repeat number within the disease-causing range, predominantly in the lower pathological range associated with elderly onset. No differences in sex, age, or body mass index were found between individuals with CAG repeat numbers within the pathological range and individuals with CAG repeat numbers within the normal or intermediate range. CONCLUSIONS AND RELEVANCE These results indicate a high prevalence of individuals carrying intermediate and pathological ranges of polyglutamine disease-associated alleles among the general population. Therefore, a substantially larger proportion of individuals than previously estimated may be at risk of developing a polyglutamine disease later in life or bearing children with a de novo mutation.

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Factors associated with HD CAG repeat instability in Huntington disease

Abstract: Significant sibling-sibling correlation for repeat instability suggests that genetic factors play a role in intergenerational CAG repeat instability.

Cited by 116 publications

References 30 publications

Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease

Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease

Common Premutations in the General Population

Prevalence of Carriers of Intermediate and Pathological Polyglutamine Disease–Associated Alleles Among Large Population-Based Cohorts

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