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

Area of Science:

• Genetics
• Neuroscience
• Pharmacogenomics

Background:

• Huntington disease (HD) is caused by a pathogenic cytosine-adenine-guanine (CAG) repeat expansion in the huntingtin gene (HTT).
• This expansion is genetically linked with single nucleotide polymorphisms (SNPs), offering potential for allele-selective therapeutic strategies.
• Identifying the frequency of specific SNPs on the mutant HTT allele is crucial for developing targeted treatments.

Purpose of the Study:

• To determine the frequency of rs362307 (SNP1) and rs362331 (SNP2) occurring on the same allele as pathogenic CAG repeat expansions in individuals with HD.
• To assess the utility of these SNPs as biomarkers for allele-selective therapies in Huntington disease.

Main Methods:

• A prospective observational study involving 202 individuals with HD across 7 US sites.
• Blood samples were analyzed using long-read sequencing and phasing to determine CAG repeat size, SNP presence/heterozygosity, and linkage to the mutant HTT allele.
• Centralized processing ensured consistent and accurate genotyping and phasing.

Main Results:

• SNP1 and/or SNP2 heterozygosity was observed in 146 (72%) of the studied individuals.
• The two studied polymorphisms were found on the mutant HTT allele in 61% of participants (95% CI: 55%-67%).
• These findings confirm the frequent co-occurrence of these SNPs with the pathogenic HTT allele.

Conclusions:

• The results support the feasibility of genotyping and phasing HTT SNPs in individuals with Huntington disease.
• Targeting specific HTT alleles based on linked SNPs is a viable strategy for personalized HD treatment.
• This approach holds promise for advancing precision medicine in the management of Huntington disease.