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Length of uninterrupted CAG repeats, independent of polyglutamine size, results in increased somatic instability and hastened age of onset in Huntington disease

By Galen E.B. Wright, Jennifer A. Collins, Chris Kay, Cassandra McDonald, Egor Dolzhenko, Qingwen Xia, Kristina Bečanović, Alicia Semaka, Charlotte M. Nguyen, Brett Trost, Fiona Richards, Emilia K. Bijlsma, Ferdinando Squitieri, Stephen W. Scherer, Michael A. Eberle, Ryan KC Yuen, Michael R. Hayden

Posted 29 Jan 2019
bioRxiv DOI: 10.1101/533414

Huntington disease (HD) is an autosomal dominant neurological disorder that is caused by a CAG repeat expansion, translated into polyglutamine, in the huntingtin (HTT) gene. Although the length of this repeat polymorphism is inversely correlated with age of onset (AOO), it does not fully explain the variability in AOO. Genomic studies have provided evidence for the involvement of DNA repair in modifying this trait, potentially through somatic repeat instability. We therefore assessed the 12bp interrupting sequence between the pathogenic CAG repeat and the adjacent polymorphic proline (CCG) tract in the HTT gene and identified variants that result in complete loss of interruption (LOI) between the HTT CAG and CCG repeats. Analysis of multiple HD pedigrees showed that this variant is associated with dramatically earlier AOO and is particularly relevant to HD patients with reduced penetrance alleles. AOO of HD is hastened by an average of 25 years in LOI carriers. This finding indicates that the number of uninterrupted CAG repeats is the most significant contributor to AOO of HD and is more impactful than polyglutamine length, which is not altered in these patients. We show that the LOI variant is associated with increases in both somatic and germline repeat instability, demonstrating a potential mechanism for this effect. Screening individuals from the general population (n=2,674 alleles) suggests that the variant occurs only in expanded CAG repeat alleles. Identification of this modifier has important clinical implications for disease management of HD families, especially for those with genotypes in the reduced penetrance ranges.

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