Exome & MiSeq sequencing of individuals with Huntington's disease

The age at onset of motor symptoms in Huntington's disease (HD) is driven by HTT CAG repeat length but modified by other genes. In this study, we used exome sequencing of 683 patients with HD with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We discovered damaging coding variants in candidate modifier genes identified in previous genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier-onset HD. Nuclease activities of purified variants in vitro correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion similar to those observed with complete FAN1 knockout. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 1 Publication

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001009077	Sequencing of Huntington's disease patient samples. Whole exome sequencing (n = 463) and MiSeq HTT amplicon sequencing (n = 584) BAM/BAI files. Two analyses (one linear and one logistic) with relevant files.	Illumina HiSeq 4000 Illumina MiSeq	363

Publications	Citations
Huntington's disease age at motor onset is modified by the tandem hexamer repeat in TCERG1. Lobanov SV, McAllister B, McDade-Kumar M, Landwehrmeyer GB, Orth M, Rosser AE, REGISTRY Investigators of the European Huntington’s disease network, Paulsen JS, PREDICT-HD Investigators of the Huntington Study Group, Lee JM, MacDonald ME, Gusella JF, Long JD, Ryten M, Williams NM, Holmans P, Massey TH, Jones L. NPJ Genom Med 7: 2022 53	4

Publications

Citations

Huntington's disease age at motor onset is modified by the tandem hexamer repeat in TCERG1.
Lobanov SV, McAllister B, McDade-Kumar M, Landwehrmeyer GB, Orth M, Rosser AE, REGISTRY Investigators of the European Huntington’s disease network, Paulsen JS, PREDICT-HD Investigators of the Huntington Study Group, Lee JM, MacDonald ME, Gusella JF, Long JD, Ryten M, Williams NM, Holmans P, Massey TH, Jones L. NPJ Genom Med 7: 2022 53