Objective: An observational research study is being conducted in patients with Huntington’s disease (HD) to determine the frequency with which the thymine (T) variant of SNP rs362307 or rs362331 occurs on the mutant huntingtin (mHTT) allele.

Background: HD is caused by a CAG triplet repeat expansion in the HTT gene, which results in production of the mHTT protein. The association of single nucleotide polymorphisms (SNPs) with the mutant HTT allele opens the possibility of selectively targeting SNPs to lower mHTT protein.

Methods: An observational research study is being conducted in approximately 200 HD patients across 7 US sites. Blood samples (DNA and RNA) are obtained at one clinic visit and processed using a three-step process. First, using the DNA samples, the number of CAG repeats is confirmed (PCR and Bioanalyzer). Second, the presence of SNPs (heterozygosity) is determined (Sanger sequencing). Third, samples for which CAG repeats are ≥36 and SNP heterozygosity are confirmed are then assessed to determine whether the targeted SNP variant is present (phased) on the mHTT allele with the expanded CAG repeat using RNA samples and a PacBio long-range sequencing investigational assay.

Results: As of February 2018, 136 HD patients have been enrolled in the study across all 7 US sites. All DNA samples have been processed. All patients had confirmation of HD diagnosis based on number of CAG repeats (≥36); the median number of CAG repeats was 44 (range, 40-62). One hundred one patients (74%) were heterozygous for SNP rs362307, SNP rs362331, or both. Phasing data were available for samples from 51 of 101 patients. Of phased samples, 44 of 51 (86%) patients had the T variant of the SNP located on the same allele as the CAG repeat (the mHTT allele) for at least one SNP.

Conclusions: Preliminary results show that the frequency of SNPs rs362307 and rs362331 in patients with HD is consistent with that reported in the literature. The ability to prospectively identify SNPs in association with the long-CAG repeat in HD patients opens the possibility of an allele-specific and personalized approach to treatment.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/prevalence-of-single-nucleotide-polymorphisms-snps-rs362307-or-rs362331-in-patients-with-huntingtons-disease/