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Am J Hum Genet. 2019 Jun 6;104(6):1116-1126. doi: 10.1016/j.ajhg.2019.04.007. Epub 2019 May 16.

Length of Uninterrupted CAG, Independent of Polyglutamine Size, Results in Increased Somatic Instability, Hastening Onset of Huntington Disease.

Author information

1
Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
2
Illumina Inc, San Diego, CA 92121, USA.
3
Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm 171 77, Sweden.
4
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
5
Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2A1, Canada.
6
The Hospital For Sick Children, The Centre for Applied Genomics, Genetics and Genome Biology, Toronto, ON M5G 0A4, Canada; University of Toronto, Department of Molecular Genetics, Toronto, ON M5G 0A4, Canada.
7
The Hospital For Sick Children, The Centre for Applied Genomics, Genetics and Genome Biology, Toronto, ON M5G 0A4, Canada.
8
Department of Clinical Genetics, Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
9
Department of Clinical Genetics, Leiden University Medical Center, Leiden 2333, the Netherlands.
10
Huntington and Rare Diseases Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo 71013, Italy.
11
The Hospital For Sick Children, The Centre for Applied Genomics, Genetics and Genome Biology, Toronto, ON M5G 0A4, Canada; University of Toronto, Department of Molecular Genetics, Toronto, ON M5G 0A4, Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5G 0A4, Canada.
12
Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada. Electronic address: mrh@cmmt.ubc.ca.

Abstract

Huntington disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Although the length of this repeat is inversely correlated with age of onset (AOO), it does not fully explain the variability in AOO. We assessed the sequence downstream of the CAG repeat in HTT [reference: (CAG)n-CAA-CAG], since variants within this region have been previously described, but no study of AOO has been performed. These analyses identified a variant that results in complete loss of interrupting (LOI) adenine nucleotides in this region [(CAG)n-CAG-CAG]. Analysis of multiple HD pedigrees showed that this LOI variant is associated with dramatically earlier AOO (average of 25 years) despite the same polyglutamine length as in individuals with the interrupting penultimate CAA codon. This LOI allele is particularly frequent in persons with reduced penetrance alleles who manifest with HD and increases the likelihood of presenting clinically with HD with a CAG of 36-39 repeats. Further, we show that the LOI variant is associated with increased somatic repeat instability, highlighting this as a significant driver of this effect. These findings indicate that the number of uninterrupted CAG repeats, which is lengthened by the LOI, is the most significant contributor to AOO of HD and is more significant than polyglutamine length, which is not altered in these individuals. In addition, we identified another variant in this region, where the CAA-CAG sequence is duplicated, which was associated with later AOO. Identification of these cis-acting modifiers have potentially important implications for genetic counselling in HD-affected families.

KEYWORDS:

CAG repeat; Huntington disease; age of onset; genetic modifier; loss of interruption; polyglutamine; reduced penetrance alleles; somatic instability

PMID:
31104771
PMCID:
PMC6556907
[Available on 2019-12-06]
DOI:
10.1016/j.ajhg.2019.04.007

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