The molecular epidemiology of Huntington disease is related to intermediate allele frequency and haplotype in the general population

Kay, Chris; Collins, Jennifer A.; Wright, Galen E.B.; Baine, Fiona; Miedzybrodzka, Zosia; Aminkeng, Folefac; Semaka, Alicia; McDonald, Cassandra; Davidson, M. J.; Madore, Steven J.; Gordon, Erynn S.; Gerry, Norman P.; Cornejo‐Olivas, Mario; Squitieri, Ferdinando; Tishkoff, Sarah A.; Greenberg, Jacquie; Krause, Amanda; Hayden, Michael R.

doi:10.1002/ajmg.b.32618

Cited by 57 publications

(52 citation statements)

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“…In contrast, previously published research 15 has shown that the A1 haplotype is associated with elongated CAG repeat lengths. 20 Finally, we identified another variant in this region that results in a longer interrupting sequence, through the insertion of a duplicate CAA-CAG motif [i.e., 18 bp; (CAA-CAG)2-CCG-CCA, Supplementary Figure S2]. In the two pedigrees where this variant was present, carriers (n=6 HD subjects) presented 4.8 years later AOO than expected in comparison to reference interrupting sequence HD subjects (AOO percentile 60th-85 th , AOO ratio P=0.04).…”

Section: The Htt Cag-ccg Loi Variant Resulting In An Uninterrupted Cmentioning

confidence: 99%

Length of uninterrupted CAG repeats, independent of polyglutamine size, results in increased somatic instability and hastened age of onset in Huntington disease

et al. 2019

Preprint

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Huntington disease (HD) is an autosomal dominant neurological disorder that is caused by a CAG repeat expansion, translated into polyglutamine, in the huntingtin (HTT) gene. Although the length of this repeat polymorphism is inversely correlated with age of onset (AOO), it does not fully explain the variability in AOO. Genomic studies have provided evidence for the involvement of DNA repair in modifying this trait, potentially through somatic repeat instability. We therefore assessed genetic variants within the 12bp interrupting sequence between the pathogenic CAG repeat and the polymorphic proline (CCG) tract in the HTT gene and identified variants that result in complete loss of interruption (LOI) between the adjacent CAG/CCG repeats.Analysis of multiple HD pedigrees showed that this variant is associated with dramatically earlier AOO and is particularly relevant to HD patients with reduced penetrance alleles. On average AOO of HD is hastened by an average of 25 years in LOI carriers. This finding indicates that the number of uninterrupted CAG repeats is the most significant contributor to AOO of HD and is more impactful than polyglutamine length, which is not altered in these patients. We show that the LOI variant is associated with increases in both somatic and germline repeat instability, demonstrating a potential mechanism for this effect. Screening individuals from the general population (n=2,674 alleles) suggests that the variant occurs only in expanded CAG repeat alleles. Identification of this modifier has important clinical implications for disease management of HD families, especially for those in the reduced penetrance ranges.3

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Section: The Htt Cag-ccg Loi Variant Resulting In An Uninterrupted Cmentioning

confidence: 99%

Length of uninterrupted CAG repeats, independent of polyglutamine size, results in increased somatic instability and hastened age of onset in Huntington disease

et al. 2019

Preprint

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“…It is important to note that few studies have reported the frequency of IAs and the prevalence of HD in large cohorts of admixed populations worldwide (Agostinho et al, ; Apolinário, Paiva, & Agostinho, ; Kay et al, ; RASKIN et al, ). A study by Kay et al () investigated the epidemiology of HD and IAs in 15 populations with different ethnic origins but did not analyze the situation in Brazil in relation to intermediate HD alleles, which was the aim of our investigation.…”

Section: Discussionmentioning

confidence: 99%

Investigation of intermediate CAG alleles of the HTT in the general population of Rio de Janeiro, Brazil, in comparison with a sample of Huntington disease‐affected families

Apolinário

Silva

Agostinho

et al. 2020

Molec Gen & Gen Med

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Background: Huntington disease (HD) (MIM: 143100) is a severe autosomal dominant neurodegenerative disease caused by the expansion of CAG trinucleotides (>35) in the HTT. Objective: To investigate the frequency of intermediate CAG alleles (IAs) in individuals residing in Rio de Janeiro city with no familial history of HD (general population, GP) in comparison with a sample of individuals from families presenting with HD who were previously investigated by our group (affected sample, AS).Results: The frequency of normal CAG alleles was 96.2%, while that of IAs was 3.6%, and that of reduced penetrance alleles was 0.2% in the GP (n = 470 chromosomes); 7.2% (17/235 individuals) of the GP presented an IA in heterozygosis with a normal allele. There was no statistically significant difference between the frequencies of the IAs in the GP and in the AS (p = .9). The most frequent haplotype per normal allele was (CAG)17-(CCG)7 (101/461) and per IA was (CAG)27-(CCG)7 (6/17) in the GP. These haplotypes were also the most frequent in the normal and IA chromosomes of the AS, respectively. Conclusion: The genetic profiles of the IAs obtained from GP and AS were rather similar. It is important to investigate the frequencies of the IAs because expansions arise from a step-by-step mechanism in which, during intergenerational transmission, large normal alleles can generate IAs, which are then responsible for generating de novo HD mutations. The genetic investigation of IAs in the GP was also important because it was focused on the population of Rio de Janeiro, an understudied group.CCG7 was the most frequent CCG allele in linkage disequilibrium with normal, intermediate, and expanded CAG alleles, similar to the Western Europe population.However, a more robust investigation, in conjunction with haplogroup determination (A, B, or C), will be required to elucidate the ancestral origin of the HTT mutations in Brazilians.

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“…Some groups have recently found a high prevalence of CAG repeats in the intermediate and reduced penetrance range in the background population 18 . There is also indication that the prevalence of HD, and frequency of new mutations, is correlated to the mean repeat number and prevalence of IAs in the general population.…”

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High frequency of intermediary alleles in the HTT gene in Northern Sweden - The Swedish Huntingtin Alleles and Phenotype (SHAPE) study

Sundblom

Niemelä

Ghazarian

et al. 2020

Sci Rep

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Trinucleotide (CAG) repeat expansions longer than 39 in the huntingtin (HTT) gene cause Huntington's disease (HD). The frequency of intermediate alleles (IA) with a length of 27-35 in the general population is not fully known, but studied in specific materials connected to the incidence of HD. The Swedish Huntingtin Alleles and phenotype (SHApe) study aims to assess the frequency of trinucleotide repeat expansions in the HTT gene in north Sweden. 8260 individuals unselected for HD from the counties of norr-and Västerbotten in the north of Sweden were included. DnA samples were obtained and analysis of the HTT gene was performed, yielding data on HTT gene expansion length in 7379 individuals. A high frequency of intermediate alleles, 6.8%, was seen. Also, individuals with repeat numbers lower than ever previously reported (<5) were found. These results suggest a high frequency of HD in the norther parts of Sweden. Subsequent analyses may elucidate the influence of IA:s on traits other than HD. Huntington's disease (HD) is caused by a CAG triplet repeat expansion, encoding polyglutamine (polyQ), in the huntingtin (HTT) gene on chromosome 4 1. The disease is inherited in an autosomal dominant fashion and leads to motor, cognitive and psychiatric symptoms, with a variable age of onset influenced by the length of the CAG repeat. Expansions with more than 39 repeats invariably cause the disease during a normal lifespan, while alleles with between 36-39 repeats are considered to confer reduced penetrance and may cause disease in an individual depending on other genetic modifiers and/or lifestyle factors 2-5. The worldwide prevalence of HD is 5.5/100 000 6 , making it a relatively common monogenic neurological disorder. The highest prevalence is found in populations with European ancestry, while for instance African and Asian populations have a much lower prevalence. As genetic tests have been widely implemented for persons at risk of HD, effort has been made to ascertain the predictive value of test results, depending on the number of repeats 2. Especially challenging in the setting of genetic testing for HD is the "gray zone" interval of 27-35 repeats, referred to as intermediate alleles (IA), that do not cause HD, but due to instability may expand to cause disease in the offspring by anticipation 7. Several hypotheses have been suggested to explain this phenomenon, including impaired DNA mismatch repair systems 8. Rare cases have been reported where the classical phenotype has presented in individuals with repeat expansion numbers in the intermediate interval 9,10. This may potentially be mediated by loss of interruption between the CAG repeat and an adjacent polymorphic proline tract (CCG) 11 .

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The molecular epidemiology of Huntington disease is related to intermediate allele frequency and haplotype in the general population

Cited by 57 publications

References 50 publications

Length of uninterrupted CAG repeats, independent of polyglutamine size, results in increased somatic instability and hastened age of onset in Huntington disease

Length of uninterrupted CAG repeats, independent of polyglutamine size, results in increased somatic instability and hastened age of onset in Huntington disease

Investigation of intermediate CAG alleles of the HTT in the general population of Rio de Janeiro, Brazil, in comparison with a sample of Huntington disease‐affected families

High frequency of intermediary alleles in the HTT gene in Northern Sweden - The Swedish Huntingtin Alleles and Phenotype (SHAPE) study

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