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

BackgroundThe 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.ObjectiveThis prospective observational study defined the frequency at which rs362307 (SNP1) or rs362331 (SNP2) was found on the same allele with pathogenic CAG expansions.MethodsAcross 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.ResultsHeterozygosity 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.ConclusionsThese 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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J04 A prospective observational study of the frequency of single nucleotide polymorphisms (SNP) in patients with huntington’s disease (hd)

10.1136/jnnp-2018-ehdn.264 ◽

2018 ◽

Author(s):

Daniel Claassen ◽

Mary Edmondson ◽

Ralf Reilmann ◽

Nenad Svrzikapa ◽

Kenneth Longo ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Observational Study ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Prospective Observational Study ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

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Potent and Selective Antisense Oligonucleotides Targeting Single-Nucleotide Polymorphisms in the Huntington Disease Gene / Allele-Specific Silencing of Mutant Huntingtin

Molecular Therapy ◽

10.1038/mt.2011.201 ◽

2011 ◽

Vol 19 (12) ◽

pp. 2178-2185 ◽

Cited By ~ 171

Author(s):

Jeffrey B Carroll ◽

Simon C Warby ◽

Amber L Southwell ◽

Crystal N Doty ◽

Sarah Greenlee ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Huntington Disease ◽

Antisense Oligonucleotides ◽

Disease Gene ◽

Mutant Huntingtin ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Allele Specific ◽

Huntington Disease Gene

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CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms

Human Molecular Genetics ◽

10.1093/hmg/10.21.2437 ◽

2001 ◽

Vol 10 (21) ◽

pp. 2437-2446 ◽

Cited By ~ 83

Author(s):

S. Choudhry

Keyword(s):

Single Nucleotide Polymorphisms ◽

Cag Repeat ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Repeat Instability

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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

10.1101/533414 ◽

2019 ◽

Cited By ~ 2

Author(s):

Galen E.B. Wright ◽

Jennifer A. Collins ◽

Chris Kay ◽

Cassandra McDonald ◽

Egor Dolzhenko ◽

...

Keyword(s):

Huntington Disease ◽

Autosomal Dominant ◽

Age Of Onset ◽

Cag Repeat ◽

Cag Repeats ◽

Repeat Polymorphism ◽

Repeat Instability ◽

Cag Repeat Expansion ◽

Genomic Studies ◽

Reduced Penetrance

ABSTRACTHuntington 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 genetic variants within the 12bp interrupting sequence between the pathogenic CAG repeat and the polymorphic proline (CCG) tract in the HTT gene and identified variants that result in complete loss of interruption (LOI) between the adjacent CAG/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. On average 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 in the reduced penetrance ranges.

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