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Updated: Dec 18, 2025
Candidate Gene Testing in Clinical Cohort Studies with Multiplexed Genotyping and Mass Spectrometry
Published on: June 21, 2018
Genotyping single nucleotide polymorphisms for allele-selective therapy in Huntington disease
Daniel O Claassen1, Jody Corey-Bloom1, E Ray Dorsey1
1Vanderbilt University Medical Center (D.O.C.), Nashville, TN; University of California San Diego (J.C.-B.), La Jolla; University of Rochester Medical Center (E.R.D.), NY; HD Reach (M.E.), Raleigh, NC; Ohio State University (S.K.K.), Columbus; University of Memphis and Veracity Neuroscience, LLC (M.S.L.), TN; George-Huntingon-Institute & Department of Clinical Radiology University of Muenster (R.R.), Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tuebingen, Germany; Havard Medical School (H.D.R.), Massachusetts General Hospital, Boston; Wake Forest University School of Medicine (F.W.), Winston Salem, NC; University of California Davis Health (V.W.), Sacramento, CA; Wave Life Sciences USA, Inc. (N.S., K.A.L., J.G., S.H., M.A.P.), Cambridge, MA; and Department of Paediatrics (N.S.), Medical Sciences Division, University of Oxford, UK.
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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