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. 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

Galen E B Wright  1 , Jennifer A Collins  1 , Chris Kay  1 , Cassandra McDonald  1 , Egor Dolzhenko  2 , Qingwen Xia  1 , Kristina Bečanović  3 , Britt I Drögemöller  4 , Alicia Semaka  5 , Charlotte M Nguyen  6 , Brett Trost  7 , Fiona Richards  8 , Emilia K Bijlsma  9 , Ferdinando Squitieri  10 , Colin J D Ross  4 , Stephen W Scherer  11 , Michael A Eberle  2 , Ryan K C Yuen  6 , Michael R Hayden  12
Affiliations

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

Galen E B Wright et al. Am J Hum Genet. .

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.

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Figures

Figure 1
Figure 1
Huntington Disease Loss of Interruption (LOI) Pedigrees Included in the Current Study Affected status, individual identifier, age-of-onset information, CAG size, and LOI genotype are indicated.
Figure 2
Figure 2
The Loss of Interruption (LOI) Variant Is Associated with an Earlier Age of Onset (AOO) in Individuals with Huntington Disease (HD) and Occurs on Expanded HTT CAG Alleles (A) The interrupting sequence between the exon one HTT CAG and CCG repeats and representative Sanger electropherograms for the reference sequence and LOI variant are shown. The interrupting sequence is depicted in blue italic font and red nucleotides show point mutations in this region that can result in the LOI variant. The dashed red box indicates the CAG repeat that is measured in diagnostic assays for HD. Nucleotides encoding the glutamine (i.e., CAG/CAA) and proline (i.e., CCG/CCA) tracts are shaded to show that the LOI variant alters the number of contiguous CAG repeats but not the number of glutamine residues in these persons. (B) The LOI is associated with earlier AOO as determined by the AOO ratio. (C) LOI carriers present with HD approximately 25 years earlier than predicted on average compared to current models for prediction of AOO. These calculations were performed using data from all HD-LOI subjects as well as mean values for each HD-LOI pedigree, versus HD subjects with the reference interrupting sequence. (D) Distribution of the HTT CAG repeat lengths in the general population ascertained through genotyping from whole-genome sequencing data. The LOI allele was detected in one research participant and was found on an intermediate allele (indicated with an arrow). Intermediate, reduced penetrance and fully penetrant alleles are shaded.
Figure 3
Figure 3
The HTT Loss-of-Interruption (LOI) Variant Is Associated with an Increased Frequency of CAG Expansions in Whole Blood (A) Somatic expansion ratio separated by CAG, corrected for age at sampling and stratified by LOI carrier status, shows that expansions are more frequent in 24 LOI carriers compared to 46 non-carriers. Standard error of the mean indicated where available. (B) Expansion ratio differences after correction for age and CAG repeat length confirms that the LOI variant is associated with increased somatic instability.
Figure 4
Figure 4
An HTT Interrupting Sequence Variant that Results in an Additional CAA-CAG Repeat Is Associated with a Later Age of Onset (AOO) in Individuals with Huntington Disease (HD) (A) The reference HTT CAG-CCG interrupting sequence in relation to the (CAA-CAG)2 variant. Nucleotides encoding the glutamine (i.e., CAG/CAA) and proline (i.e., CCG/CCA) tracts are shaded. (B) The (CAA-CAG)2 variant is associated with later AOO as determined by the AOO ratio in HD subjects compared to HD subjects with the reference interrupting sequence. (CAA-CAG)2 carriers present on average 4.2 years later than the majority of individuals with HD with the reference CAG repeat interruption.
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