Huntington disease reduced penetrance alleles occur at high frequency in the general population

Kay, Chris; Collins, Jennifer A.; Miedzybrodzka, Zosia; Madore, Steven J.; Gordon, Erynn S.; Gerry, Norman P.; Davidson, M. J.; Slama, Ramy; Hayden, Michael R.

doi:10.1212/wnl.0000000000002858

Cited by 88 publications

(61 citation statements)

References 31 publications

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“…Participants were not recruited on the presence or absence of any disease phenotype. 3,907 individuals were genotyped from the CPMC cohort as previously described (Kay, Collins, et al, ), of whom 3,221 provided data on self‐declared ethnicity. Individuals with self‐declared ethnicity as Hispanic American, African‐American, or East Asian were used for subpopulation analysis of CAG repeat length by ancestry.…”

Section: Methodsmentioning

confidence: 99%

“…Intermediate alleles (IAs), defined as 27–35 CAG repeats, have the potential for germline expansion into the HD range, with risk of expansion increasing across the IA repeat range (Semaka, Creighton, Warby, & Hayden, ; Semaka, Kay, Doty, Collins, Bijlsma, et al, ). IA frequency has been estimated from 2.9% to 3.4% of alleles in representative population samples of European ancestry, with an IA genotype in as many as one in 15 individuals from the general population (i.e., approximately 3.3% allele frequency, which corresponds to a 6.7% genotypic or carrier frequency among individuals in the population) (Kay, Collins, et al, ; Ramos et al, ; Semaka, Kay, Doty, Collins, Tam, et al, ; Sequeiros et al, ). The dramatically lower prevalence of HD in non‐European populations may result from a lower IA frequency and hence a lower new mutation rate in these ancestry groups, with fewer CAG expansion events and a consequent lower incidence of the disease (Andrew & Hayden, ).…”

Section: Introductionmentioning

confidence: 99%

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

Kay

Collins

Wright

et al. 2018

American J of Med Genetics Pt B

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Huntington disease (HD) is the most common monogenic neurodegenerative disorder in populations of European ancestry, but occurs at lower prevalence in populations of East Asian or black African descent. New mutations for HD result from CAG repeat expansions of intermediate alleles (IAs), usually of paternal origin. The differing prevalence of HD may be related to the rate of new mutations in a population, but no comparative estimates of IA frequency or the HD new mutation rate are available. In this study, we characterize IA frequency and the CAG repeat distribution in fifteen populations of diverse ethnic origin. We estimate the HD new mutation rate in a series of populations using molecular IA expansion rates. The frequency of IAs was highest in Hispanic Americans and Northern Europeans, and lowest in black Africans and East Asians. The prevalence of HD correlated with the frequency of IAs by population and with the proportion of IAs found on the HD-associated A1 haplotype. The HD new mutation rate was estimated to be highest in populations with the highest frequency of IAs. In European ancestry populations, one in 5,372 individuals from the general population and 7.1% of individuals with an expanded CAG repeat in the HD range are estimated to have a molecular new mutation. Our data suggest that the new mutation rate for HD varies substantially between populations, and that IA frequency and haplotype are closely linked to observed epidemiological differences in the prevalence of HD across major ancestry groups in different countries.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Kay

Collins

Wright

et al. 2018

American J of Med Genetics Pt B

Self Cite

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“…The normal HTT gene contains from 5 to 35 stable CAG repeats, while the majority of HD patients have expanded repeats of above 40 CAG units that are fully penetrant. In rare cases, HD symptoms are associated with small CAG repeats from 36 to 39 CAG, which show low penetrance [9,10]. Abnormal CAG repeat tracts become unstable in the germline, with a striking tendency toward expansions.…”

Section: Genetic Of Hdmentioning

confidence: 99%

Genetic Modifiers of CAG.CTG Repeat Instability in Huntington's Disease Mouse Models

Dandelot¹,

Tomé²

2017

Huntington's Disease - Molecular Pathogenesis and Current Models

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Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder whose characterstics were first described by George Huntington in 1872. Several decades later, in 1993, the mutation behind this disease was found to be an unstable expanded CAG repeat within exon 1 of the HTT gene localized on the short arm of chromosome 4. The majority of HD patients carry more than 40 CAG repeats, which become unstable and usually increase in size in successive generations and in tissues. In order to dissect the molecular mechanisms underlying CAG repeat instability, several HD mouse models have been created in the 1990s. Significant data have revealed that the absence of proteins from the mismatch repair (MMR) or the base and nucleotide excision repair decreased the pathogenic expansion-biased somatic mosaicism and/or intergenerational expansions. Some polymorphic variants of MMR genes have also been associated with reduced somatic expansions. Since expansionbiased somatic mosaicism likely contributes to disease manifestations, these results suggest that genetic modifiers of instability may also affect disease severity. In this chapter, we provide an overview of the data recently published about DNA instability; the roles of genetic modifiers of trinucleotide repeat dynamics in mouse models; and the possible therapeutic interventions.

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“…Whereas, healthy subjects have fewer than 35 CAG repeats, HD patients range from 35 up to ∼200, and repeat size correlates with the age of disease onset (1). HD is invariably fatal and a recent study showed that prevalence is higher than previously thought, with 1 in 400 being at risk of developing HD (6). There is currently no treatment that targets the molecular cause of the disease, although several approaches are in development that specifically target the pathological mutant Huntingtin gene (HTT) (7); these include novel gene therapy tools such as synthetic zinc finger proteins (8).…”

Section: Introductionmentioning

confidence: 99%

Prevalence of Non-psychiatric Comorbidities in Pre-symptomatic and Symptomatic Huntington's Disease Gene Carriers in Poland

et al. 2020

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Huntington's disease (HD) is monogenic neurodegenerative disorder caused by CAG expansions within the Huntingtin gene (Htt); it has a prevalence of 1 in 10,000 worldwide and is invariably fatal. Typically, healthy individuals have fewer than 35 CAG repeats, while the CAG expansions range from 36 to ∼200 in HD patients. The hallmark of HD is neurodegeneration, especially in the striatal nuclei, basal ganglia and cerebral cortex, leading to neurological symptoms that involve motor, cognitive, and psychiatric events. However, HD is a complex disorder that may also affect peripheral organs, so it is possible that HD patients could be affected by comorbidities. Hence, we investigated the prevalence of comorbid conditions in HD patients (pre-symptomatic and symptomatic groups) and compared the frequency of those conditions to a control group. Our groups represent 65% of HD gene carriers registered in Poland. We identified 8 clusters of comorbid conditions in both HD groups, namely: musculoskeletal, allergies, cardiovascular, neurological, gastrointestinal, thyroid, psychiatric, and ophthalmologic. We found that HD patients have a significantly higher percentage of co-existing conditions in comparison to the control group. Among the 8 clusters of diseases, musculoskeletal, psychiatric, and cardiovascular events were significantly more frequent in both pre-and symptomatic HD patients, while neurological and gastrointestinal clusters showed significantly higher occurrence in the HD symptomatic group. A greater recognition of comorbidity in HD might help to better understand health outcomes and improve clinical management.

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Huntington disease reduced penetrance alleles occur at high frequency in the general population

Abstract: HD alleles with a CAG repeat length of 36-38 occur at high frequency in the general population. The infrequent diagnosis of HD at this CAG length is likely due to low penetrance. Another important contributing factor may be reduced ascertainment of HD in those of older age.

Cited by 88 publications

References 31 publications

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

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

Genetic Modifiers of CAG.CTG Repeat Instability in Huntington's Disease Mouse Models

Prevalence of Non-psychiatric Comorbidities in Pre-symptomatic and Symptomatic Huntington's Disease Gene Carriers in Poland

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