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Estimating the probability of de novo HD cases from transmissions of expanded penetrant CAG alleles in the Huntington disease gene from male carriers of high normal alleles (27-35 CAG).

ABSTRACT: Huntington disease (HD) is a dominantly transmitted neurodegenerative disorder that arises from expansion of a CAG trinucleotide repeat on chromosome 4p16.3. CAG repeat allele lengths are defined as fully penetrant at >or=40, reduced penetrance at 36-39, high normal at 27-35, and normal at or=36) to offspring. We estimated the conditional probability of an offspring inheriting an expanded penetrant allele given a father with a high normal allele by applying probability definitions and rules to estimates of HD incidence, paternal birth rate, frequency of de novo HD, and frequency of high normal alleles in the general population. The estimated probability that a male high normal allele carrier will have an offspring with an expanded penetrant allele ranges from 1/6,241 to 1/951. These estimates may be useful in genetic counseling for male high normal allele carriers.

SUBMITTER: Hendricks AE

PROVIDER: S-EPMC2724761 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Estimating the probability of de novo HD cases from transmissions of expanded penetrant CAG alleles in the Huntington disease gene from male carriers of high normal alleles (27-35 CAG).

Hendricks Audrey E AE Latourelle Jeanne C JC Lunetta Kathryn L KL Cupples L Adrienne LA Wheeler Vanessa V MacDonald Marcy E ME Gusella James F JF Myers Richard H RH

American journal of medical genetics. Part A 20090701 7

Huntington disease (HD) is a dominantly transmitted neurodegenerative disorder that arises from expansion of a CAG trinucleotide repeat on chromosome 4p16.3. CAG repeat allele lengths are defined as fully penetrant at >or=40, reduced penetrance at 36-39, high normal at 27-35, and normal at <or=26. Fathers, but not mothers, with high normal alleles are at risk of transmitting potentially penetrant HD alleles (>or=36) to offspring. We estimated the conditional probability of an offspring inheritin ...[more]

PMID: 19507258

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Project description:ImportanceIn Huntington disease (HD), mutation severity is defined by the length of the CAG trinucleotide sequence, a well-known predictor of clinical onset age. The association with disease trajectory is less well characterized. Quantifiable summary measures of trajectory applicable over decades of early disease progression are lacking. An accurate model of the age-CAG association with early progression is critical to clinical trial design, informing both sample size and intervention timing.ObjectiveTo succinctly capture the decades-long early progression of HD and its dependence on CAG repeat length.Design, setting, and participantsProspective study at 4 academic HD treatment and research centers. Participants were the combined sample from the TRACK-HD and Track-On HD studies consisting of 290 gene carriers (presymptomatic to stage II), recruited from research registries at participating centers, and 153 nonbiologically related controls, generally spouses or friends. Recruitment was targeted to match a balanced, prespecified spectrum of age, CAG repeat length, and diagnostic status. In the TRACK-HD and Track-On HD studies, 13 and 5 potential participants, respectively, failed study screening. Follow-up ranged from 0 to 6 years. The study dates were January 2008 to November 2014. These analyses were performed between December 2015 and January 2019.Main outcomes and measuresThe outcome measures were principal component summary scores of motor-cognitive function and of brain volumes. The main outcome was the association of these scores with age and CAG repeat length.ResultsWe analyzed 2065 visits from 443 participants (247 female [55.8%]; mean [SD] age, 44.4 [10.3] years). Motor-cognitive measures were highly correlated and had similar CAG repeat length-dependent associations with age. A composite summary score accounted for 67.6% of their combined variance. This score was well approximated by a score combining 3 items (total motor score, Symbol Digit Modalities Test, and Stroop word reading) from the Unified Huntington's Disease Rating Scale. For either score, initial progression age and then acceleration rate were highly CAG repeat length dependent. The acceleration continues through at least stage II disease. In contrast, 3 distinct patterns emerged among brain measures (basal ganglia, gray matter, and a combination of whole-brain, ventricular, and white matter volumes). The basal ganglia pattern showed considerable change in even the youngest participants but demonstrated minimal acceleration of loss with aging. Each clinical and brain summary score was strongly associated with the onset and rate of decline in total functional capacity.Conclusions and relevanceResults of this study suggest that succinct summary measures of function and brain loss characterize HD progression across a wide disease span. CAG repeat length strongly predicts their decline rate. This work aids our understanding of the age and CAG repeat length-dependent association between changes in the brain and clinical manifestations of HD.

Dataset Information

Estimating the probability of de novo HD cases from transmissions of expanded penetrant CAG alleles in the Huntington disease gene from male carriers of high normal alleles (27-35 CAG).

Publications

Estimating the probability of de novo HD cases from transmissions of expanded penetrant CAG alleles in the Huntington disease gene from male carriers of high normal alleles (27-35 CAG).

Similar Datasets

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