CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease

Semaka, Alicia; Kay, Chris; Doty, Crystal N.; Collins, Jennifer A.; Bijlsma, Emilia K.; Richards, Fiona; Goldberg, Y P; Hayden, Michael R.

doi:10.1136/jmedgenet-2013-101796

Cited by 70 publications

(74 citation statements)

References 27 publications

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“…The longer is the CAG expansion, the higher will be the chance of transmission of an expanded allele to the next generation (Nahhas et al, 2005;Wheeler et al, 2007;Warby et al, 2009). The risk of transmitting an expanded allele, with complete penetrance, to the offspring is higher when the IA shows more than 30 CAG repeats (Semaka et al, 2013a).…”

Section: Introductionmentioning

confidence: 99%

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REVIEW-ARTICLE Intermediate alleles of Huntington’s disease HTT gene in different populations worldwide: a systematic review

2017

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ABSTRACT. Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder caused by a dynamic mutation due to the expansion of CAG repeats in the HTT gene (4p16.3). The considered normal alleles have less than 27 CAG repeats. Intermediate alleles (IAs) show 27 to 35 CAG repeats and expanded alleles have more than 35 repeats. The IAs apparently have shown a normal phenotype. However, there are some reported associations between individuals that bear an IA and clinical HD signs, such as behavioral disturbs. The association of IAs with the presence of clinical signs gives clinical relevance to these patients. We emphasized the importance of determining the frequency of IA alleles in the general population as well as in HD families. Therefore, the aim of this study was to conduct a systematic review, in order to investigate the frequency of IAs in the overall chromosomes of different ethnic groups and of families with HD history worldwide as well as the frequency of individuals who bear the intermediate alleles. We searched indexed articles from the following electronic databases: U.S. National Library of Medicine and the National Institutes of Health (PubMed), Pubmed Central (PMC) and Virtual Health Library (VHL). Therefore, 488 articles were obtained and, of these, 33 had been published in more than one database. We accepted the article of only one database and ended up with 455 articles for this review. The frequency of IAs within the chromosomes of the general population ranged from 0.45 to 8.7% and of individuals with family history of HD ranged from 0.05 to 5.1%. The higher frequency of IAs in the general population (8.7%) was found in one Brazilian cohort.

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Section: Introductionmentioning

confidence: 99%

“…Therefore, the estimate of this frequency will be useful for the knowledge of the epidemiological profile of HD in Brazil. To our knowledge the prevalence of HD for the overall population in Brazil has not yet been estimated (Goldberg et al, 1993;Feigin, 2013;Semaka et al, 2013a;Agostinho et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

REVIEW-ARTICLE Intermediate alleles of Huntington’s disease HTT gene in different populations worldwide: a systematic review

2017

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“…Even if these allele sizes are associated with low penetrance, they are pathological and risk to expand further upon transmission. 28 As we found a similar proportion of carriers of HD-causing CAG expansions in an independent cohort affected with inherited ataxia (1:541; EUROSCA cohort; data not shown), Data are estimate ± SE per 10 additional repeat or if at least one allele over 27 repeats (ANOVA with sandwich estimator taking into account family effect); P-value. it is less expected that the high prevalence is specific to cancer population.…”

Section: Discussionmentioning

confidence: 62%

CAG repeat size in Huntingtin alleles is associated with cancer prognosis

et al. 2016

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The abnormal expansion of a ≥ 36 CAG unit tract in the Huntingtin gene (HTT) leads to Huntington's disease (HD), but has also been associated with cancer: the incidence of cancer is lower in HD patients than in age-matched controls, but HD-causing variants of HTT accelerate the progression of breast tumors and the development of metastases in mouse models of breast cancer. To investigate the relationship between HTT CAGs and cancer, data concerning 2407 women with BRCA1 or BRCA2 mutations that predispose to breast and ovarian cancers and 431 patients with breast cancer without family histories were studied; the size of the CAG expansions on both HTT alleles was determined in each subject. The proportion of individuals carrying a CAG expansion in a pathological range for HD was 10 times more frequent than previously reported in the literature. In carriers of BRCA2 mutations, the length of the HTT CAG tract was correlated with lower incidence of ovarian cancer. Among carriers of BRCA1 mutations who developed a breast cancer, its onset occurred 2.4 years earlier in individuals with intermediate HTT alleles (≥27) than in those with a CAG tract o27. Finally, in patients with sporadic HER2 breast cancer, metastasis increased by a factor of 11.10 per 10 additional CAG repeats in HTT. We concluded that whereas long CAG length could be associated with lower cancer incidence, it could also be paradoxically associated with cancer severity (age of apparition and metastasis development).

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“…[1989] Discusses requests for predictive testing of affected individuals, minors, impact on relatives, use of research samples for clinical purposes Demyttenaere et al [1992] Discusses challenging counseling situations Harper and Newcombe [1992] Use of life table risk estimates in counseling; anticipates the report of Brinkman et al [1997] Heimler andZanko [1995], Reich et al [1996] Case report of testing monozygotic twins Mehlman et al [1996], Burgess et al [1997], Uhlmann et al [1996], Visintainer et al [2001] Anonymous testing Alford et al [1996] Challenging laboratory and clinical scenarios Almqvist et al [1997] Discusses the impact of the unusual situation of a reversal of risk between a linkage analysis and direct gene analysis Maat-Kievit et al [1999b], Benjamin and Lashwood [2000], Lindblad [2001] Testing individuals at 25% risk Alonso et al [2002], Squitieri et al [2003] Counseling about unexpected homozygosity for an expanded allele; predictive testing for patients at risk for homozygosity Nahhas et al [2009] Contraction of an abnormal allele into the reduced penetrance range Hendricks et al [2009] Estimating the probability of de novo HD in the children of male carriers of high-normal alleles Sequeiros et al [2010], Semaka et al [2013c] Frequency of intermediate and reduced penetrance alleles Chen et al [2012] Use of a novel model for estimating genetic risk incorporating family information Palomaki and Richards [2012] Laboratory proficiency testing Semaka et al [2013a] Patient comprehension of the implications of an intermediate allele Squitieri and Jankovic [2012], Ha et al [2012] Possibility of a phenotype associated with CAG repeat lengths of 27-35 Semaka et al [2013bSemaka et al [ , 2015, Semaka and Hayden (2014) CAG size-specific risk estimates for intermediate allele repeat instability; counseling implications; case report of expansion of a maternal intermediate allele Bean and Bayrak-Toydemir [20...…”

Section: Where Is This All Going? Discussion and Summarymentioning

confidence: 99%

Genetic counseling and testing for Huntington's disease: A historical review

Nance

2016

American J of Med Genetics Pt B

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This manuscript describes the ways in which genetic counseling has evolved since John Pearson and Sheldon Reed first promoted "a genetic education" in the 1950s as a voluntary, non-directive clinical tool for permitting individual decision making. It reviews how the emergence of Huntington's disease (HD) registries and patient support organizations, genetic testing, and the discovery of a disease-causing CAG repeat expansion changed the contours of genetic counseling for families with HD. It also reviews the guidelines, outcomes, ethical and laboratory challenges, and uptake of predictive, prenatal, and preimplantation testing, and it casts a vision for how clinicians can better make use of genetic counseling to reach a broader pool of families that may be affected by HD and to ensure that genetic counseling is associated with the best levels of care.

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CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease

Abstract: These data provide novel insights into the origins of new mutations for HD. The CAG size-specific risk estimates inform clinical practice and provide accurate risk information for persons who receive an IA predictive test result.

Cited by 70 publications

References 27 publications

REVIEW-ARTICLE Intermediate alleles of Huntington’s disease HTT gene in different populations worldwide: a systematic review

REVIEW-ARTICLE Intermediate alleles of Huntington’s disease HTT gene in different populations worldwide: a systematic review

CAG repeat size in Huntingtin alleles is associated with cancer prognosis

Genetic counseling and testing for Huntington's disease: A historical review

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