RT Journal Article
SR Electronic
T1 Genotyping single nucleotide polymorphisms for allele-selective therapy in Huntington disease
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams & Wilkins
SP e430
DO 10.1212/NXG.0000000000000430
VO 6
IS 3
A1 Daniel O. Claassen
A1 Jody Corey-Bloom
A1 E. Ray Dorsey
A1 Mary Edmondson
A1 Sandra K. Kostyk
A1 Mark S. LeDoux
A1 Ralf Reilmann
A1 H. Diana Rosas
A1 Francis Walker
A1 Vicki Wheelock
A1 Nenad Svrzikapa
A1 Kenneth A. Longo
A1 Jaya Goyal
A1 Serena Hung
A1 Michael A. Panzara
YR 2020
UL http://ng.neurology.org/content/6/3/e430.abstract
AB 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.CAG=cytosine-adenine-guanine; HD=Huntington disease; mHTT=mutant HTT; SNP=single nucleotide polymorphism; wtHTT=wild-type HTT; UHDRS=Unified Huntington Disease Rating Scale