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UBC Theses and Dissertations

Genetic counselling implications for intermediate allele predictive test results for Huntington disease Semaka, Alicia Joy

Abstract

Intermediate alleles (IAs) for Huntington disease (HD) have between 27–35 CAG repeats. While they usually do not confer the HD phenotype, they are prone to germline CAG repeat instability. Consequently, offspring are at-risk of inheriting an expanded allele in the HD range (≥36 CAG). Currently there are numerous gaps in our molecular and clinical knowledge on IAs despite their characterization almost 20 years ago. This thesis utilized a unique mixed-method design of molecular and qualitative techniques in order to generate new knowledge on the frequency, haplotype, and CAG repeat instability of IAs and explored current genetic counselling practices and patient understanding and interpretation of an IA predictive test results (PTR). In the Huntington Disease Biobank at the University of British Columbia, 30% (n=54/181) of IA familial transmissions demonstrated intergenerational CAG repeat instability. Of these unstable transmissions, 14% were repeat expansions into the disease-associated range. In a sample of British Columbia’s general population, with no known association to HD, 5.8% (n=92/1594) of individuals were found to have an IA. Of the IAs ascertained in this general population sample, 60% were on haplotypes associated with a high-risk of CAG repeat instability. Paternal CAG-size specific risk estimates for repeat instability, including repeat expansion into the HD range, were established using sperm (n=18763) from 31 males with an IA. Alleles at the upper limits of the intermediate CAG size range (34-35 CAG) had the most significant risk (i.e. 2.5-21.0%) of expanding into the disease range. Interviews with medical genetics service providers and individuals who received an IA-PTR revealed pre-test genetic counselling practices vary based on the individuals’ family history and that clients struggled to understand the clinical implications and significance of their IA-PTR. This thesis substantially contributes to our knowledge of IAs for HD. Collectively the comprehensive findings have important implications for genetic counselling and will help ensure individuals undergoing predictive testing receive appropriate support, education, and counselling on IAs.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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