A CIS-acting Modifier of Age at Diagnosis of Huntington Disease in Black South African Patients

Levesley, J., Baine, F., Ciosi, M. , Maxwell, A. , Monckton, D. G. and Krause, A. (2018) A CIS-acting Modifier of Age at Diagnosis of Huntington Disease in Black South African Patients. EHDN 2018 Plenary Meeting, Vienna, Austria, 14-16 Sep 2018.

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Abstract

Background: Huntington disease (HD) is a dominantly inherited neurodegenerative disorder, presenting with a movement disorder, cognitive decline and psychiatric complications. HD is caused by the expansion of a CAG repeat tract in exon 1 of the huntingtin gene (HTT). In other repeat expansion disorders, variants within the associated repeat tracts may affect stability, which in turn modifies disease severity. Although sequence variation has been reported within the sequence encoding the HTT polyglutamine and polyproline tract, little is known about its effect on disease. Aim: To determine the sequence diversity precisely within the HTT exon 1 trinucleotide repeat in black South African individuals and assess the effect of sequence variation in modifying disease. Methods/techniques: A sample of black South African individuals (59 patients and 153 controls) was analysed using a specialised high-throughput DNA sequencing assay and data analysis pipeline, specific for the HTT exon 1 repeat. Results/outcomes: Significant diversity was observed in comparison to a European sample of patients, with novel African alleles defined by the description of allele sub-structures. The most common disease allele structure in our patients was associated with the absence of the CCGCCA cassette that precedes the polyproline CCG repeat in typical HD-causing alleles. Regression analysis determined that age at diagnosis was approximately 6 to 13 years earlier in patients carrying HD-causing alleles lacking the CCGCCA cassette. Conclusion: This is the first study to describe allele sequence diversity within the HTT exon 1 repeat in an African population. The absence of the CCGCCA cassette, which appears to be African-specific and associated with an earlier age at diagnosis in African HD patients, is a potential cis-acting modifier of HD onset.

Item Type:Conference or Workshop Item
Additional Information:Abstract published in Journal of Neurology, Neurosurgery and Psychiatry 89(S1):A27-A28.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Maxwell, Mr Alastair and Levesley, Jessica and Monckton, Professor Darren and Ciosi, Dr Marc
Authors: Levesley, J., Baine, F., Ciosi, M., Maxwell, A., Monckton, D. G., and Krause, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology

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