The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease

Andrew, Susan E.; Goldberg, Y P; Kremer, Berry; Telenius, H; Theilmann, Jane; Adam, Shelin; Starr, Elizabeth; Squitieri, Ferdinando; Lin, B.; Kalchman, Michael A.

doi:10.1038/ng0893-398

Cited by 985 publications

(567 citation statements)

References 20 publications

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“…1,2 HD usually manifests in patients between 35 and 55 years of age, 3,4 and average life expectancy is 15 to 20 years after the onset of the disease. The prevalence of HD varies with ethnicity.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…HD alleles have 36 CAGs in the HD gene (also called IT15), while normal individuals have between 10-35 CAG units (Huntington's Disease Collaborative Research Group, 1993). The severity and age at onset of HD inversely correlates with CAG repeat length; longer repeats cause an earlier age of onset (Andrew et al, 1993;Brandt et al, 1996;Brinkman et al, 1997). HD is characterized by uncontrolled movements (chorea), accompanied with cognitive and/or psychiatric distrurbances (Andrew et al, 1993;Cummings, 1993;Brandt et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…The severity and age at onset of HD inversely correlates with CAG repeat length; longer repeats cause an earlier age of onset (Andrew et al, 1993;Brandt et al, 1996;Brinkman et al, 1997). HD is characterized by uncontrolled movements (chorea), accompanied with cognitive and/or psychiatric distrurbances (Andrew et al, 1993;Cummings, 1993;Brandt et al, 1996). Since the first symptoms usually present between 35 and 45 years of age, when most families already have their children, genetic counseling has been an important but delicate issue.…”

Section: Introductionmentioning

confidence: 99%

Genetic background of Huntington disease in Croatia: Molecular analysis of CAG, CCG, and ?2642 (E2642del) polymorphisms

Hečimović

Klepac

et al. 2002

Hum. Mutat.

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This study presents the first molecular data on the basis and the origin of Huntington disease in Croatia and is the first such analysis performed among a Slavic population. We analyzed three trinucleotide polymorphisms in the HD gene: CAG, CCG and GAG ∆2642 (E2642del) triplets. Analysis of the CAG repeat size among 44 Huntington patients (39-66 CAGs) and 51 normal individuals (9-34 CAGs) showed that the range of the repeats was similar to previous findings. The frequency of the CCG and ∆2642 polymorphic alleles on N and HD chromosomes was found to correlate well with earlier reports for Western European populations. We found significance for both the CCG7 allele (p=0.004) and the ∆2642 allele (p<0.001) among HD chromosomes. The CCG7 allele was overpresented among affected chromosomes (94.6%), but was also the most frequent CCG allele among normal chromosomes (66.7%). Interestingly, the ∆2642 allele was present on 40.5% HD chromosomes compared to only 9.8% of control chromosomes. Our results indicate that HD mutations in Croatia could be of the same origin as in Western populations and also support the multi-step hypothesis for generating new HD alleles. Similar frequencies and distributions of both the CCG and the ∆2642 polymorphisms in Croatia and Western European normal chromosomes indicate that the prevalence rate of HD in Croatia may be as high as in Western populations. Since we estimated a lower prevalence rate (1 : 100,000), we assume that there are still many misdiagnosed and/or unrecognized cases of Huntington disease in Croatia.

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“…Currently, proximity to clinical diagnosis is estimated using statistical models based upon CAG repeat length and age 4, 6. However, the CAG repeat length only accounts for between 50% and 69% of the variance observed in age at diagnosis 6, 7, 8. Consequently, the statistical estimations of proximity to diagnosis are unreliable at the level of the individual,5 resulting in the need for increased sample sizes to adequately power premanifest clinical trials.…”

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Predicting clinical diagnosis in Huntington's disease: An imaging polymarker

Mason

Daws

Soreq

et al. 2018

Annals of Neurology

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ObjectiveHuntington's disease (HD) gene carriers can be identified before clinical diagnosis; however, statistical models for predicting when overt motor symptoms will manifest are too imprecise to be useful at the level of the individual. Perfecting this prediction is integral to the search for disease modifying therapies. This study aimed to identify an imaging marker capable of reliably predicting real‐life clinical diagnosis in HD.MethodA multivariate machine learning approach was applied to resting‐state and structural magnetic resonance imaging scans from 19 premanifest HD gene carriers (preHD, 8 of whom developed clinical disease in the 5 years postscanning) and 21 healthy controls. A classification model was developed using cross‐group comparisons between preHD and controls, and within the preHD group in relation to “estimated” and “actual” proximity to disease onset. Imaging measures were modeled individually, and combined, and permutation modeling robustly tested classification accuracy.ResultsClassification performance for preHDs versus controls was greatest when all measures were combined. The resulting polymarker predicted converters with high accuracy, including those who were not expected to manifest in that time scale based on the currently adopted statistical models.InterpretationWe propose that a holistic multivariate machine learning treatment of brain abnormalities in the premanifest phase can be used to accurately identify those patients within 5 years of developing motor features of HD, with implications for prognostication and preclinical trials. Ann Neurol 2018;83:532–543

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The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease

Cited by 985 publications

References 20 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

Genetic background of Huntington disease in Croatia: Molecular analysis of CAG, CCG, and ?2642 (E2642del) polymorphisms

Predicting clinical diagnosis in Huntington's disease: An imaging polymarker

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