Genetic counselling implications for intermediate allele predictive test results for Huntington disease

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.Medicine, Faculty ofMedical Genetics, Department ofGraduat

A new mutation for Huntington disease following maternal transmission of an intermediate allele

New mutations for Huntington disease (HD) originate from CAG repeat expansion of intermediate alleles (27-35 CAG). Expansions of such alleles into the pathological range (≥ 36 CAG) have been exclusively observed in paternal transmission. We report the occurrence of a new mutation that defies the paternal expansion bias normally observed in HD. A maternal intermediate allele with 33 CAG repeats expanded in transmission to 48 CAG repeats causing a de novo case of HD in the family. Retrospectively, the mother presented with cognitive decline, but HD was never considered in the differential diagnosis. She was diagnosed with dementia and testing for HD was only performed after her daughter had been diagnosed. This observation of an intermediate allele expanding into the full penetrance HD range after maternal transmission has important implications for genetic counselling of females with intermediate repeat

Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes

<p>Huntington disease (HD) is a neurodegenerative disorder resulting from the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. Worldwide prevalence varies geographically with the highest figures reported in populations of European ancestry. HD in South Africa has been reported in Caucasian, black and mixed subpopulations, with similar estimated prevalence in the Caucasian and mixed groups and a lower estimate in the black subpopulation. Recent studies have associated specific HTT haplotypes with HD in distinct populations. Expanded HD alleles in Europe occur predominantly on haplogroup A (specifically high-risk variants A1/A2), whereas in East Asian populations, HD alleles are associated with haplogroup C. Whether specific HTT haplotypes associate with HD in black Africans and how these compare with haplotypes found in European and East Asian populations remains unknown. The current study genotyped the HTT region in unaffected individuals and HD patients from each of the South African subpopulations, and haplotypes were constructed. CAG repeat sizes were determined and phased to haplotype. Results indicate that HD alleles from Caucasian and mixed patients are predominantly associated with haplogroup A, signifying a similar European origin for HD. However, in black patients, HD occurs predominantly on haplogroup B, suggesting several distinct origins of the mutation in South Africa. The absence of high-risk variants (A1/A2) in the black subpopulation may also explain the reported low prevalence of HD. Identification of haplotypes associated with HD-expanded alleles is particularly relevant to the development of population-specific therapeutic targets for selective suppression of the expanded HTT transcript.</p>