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. 2020 May 14;6(3):e430.
doi: 10.1212/NXG.0000000000000430. eCollection 2020 Jun.

Genotyping single nucleotide polymorphisms for allele-selective therapy in Huntington disease

Daniel O Claassen  1 , Jody Corey-Bloom  1 , E Ray Dorsey  1 , Mary Edmondson  1 , Sandra K Kostyk  1 , Mark S LeDoux  1 , Ralf Reilmann  1 , H Diana Rosas  1 , Francis Walker  1 , Vicki Wheelock  1 , Nenad Svrzikapa  1 , Kenneth A Longo  1 , Jaya Goyal  1 , Serena Hung  1 , Michael A Panzara  1
Affiliations

Genotyping single nucleotide polymorphisms for allele-selective therapy in Huntington disease

Daniel O Claassen et al. Neurol Genet. .

Abstract

Background: The huntingtin gene (HTT) pathogenic cytosine-adenine-guanine (CAG) repeat expansion responsible for Huntington disease (HD) is phased with single nucleotide polymorphisms (SNPs), providing targets for allele-selective treatments.

Objective: This prospective observational study defined the frequency at which rs362307 (SNP1) or rs362331 (SNP2) was found on the same allele with pathogenic CAG expansions.

Methods: Across 7 US sites, 202 individuals with HD provided blood samples that were processed centrally to determine the number and size of CAG repeats, presence and heterozygosity of SNPs, and whether SNPs were present on the mutant HTT allele using long-read sequencing and phasing.

Results: Heterozygosity of SNP1 and/or SNP2 was identified in 146 (72%) individuals. The 2 polymorphisms were associated only with the mHTT allele in 61% (95% high density interval: 55%, 67%) of individuals.

Conclusions: These results are consistent with previous reports and demonstrate the feasibility of genotyping, phasing, and targeting of HTT SNPs for personalized treatment of HD.

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Figures

Figure 1
Figure 1. Phasing results
HDI = high-density interval.
Figure 2
Figure 2. Length of CAG repeats among population with HD
The normal allele with 18 CAG repeats and the mutant allele with 43 CAG repeats were shown to be the frequently occurring genotype for HTT in the patients tested. The data did not pass the normal distribution using the Shapiro-Wilk normality test.
See this image and copyright information in PMC

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