Blood DNA methylation provides an accurate biomarker of KMT2B-related dystonia and predicts onset

25Citations
Citations of this article
24Readers
Mendeley users who have this article in their library.

Abstract

Dystonia is a prevalent, heterogeneous movement disorder characterized by involuntarily abnormal postures. Biomarkers of dystonia are notoriously lacking. Here, a biomarker is reported for histone lysine methyltransferase (KMT2B)-deficient dystonia, a leading subtype among the individually rare monogenic dystonias. It was derived by applying a support vector machine to an episignature of 113 DNA CpG sites, which, in blood cells, showed significant epigenome-wide association with KMT2B deficiency and at least 1× log-fold change of methylation. This classifier was accurate both when tested on the general population and on samples with various other deficiencies of the epigenetic machinery, thus allowing for definitive evaluation of variants of uncertain significance and identifying patients who may profit from deep brain stimulation, a highly successful treatment in KMT2B-deficient dystonia. Methylation was increased in KMT2B deficiency at all 113 CpG sites. The coefficients of variation of the normalized methylation levels at these sites also perfectly classified the samples with KMT2B-deficient dystonia. Moreover, the mean of the normalized methylation levels correlated well with the age at onset of dystonia (P = 0.003) - being lower in samples with late or incomplete penetrance - thus serving as a predictor of disease onset and severity. Similarly, it may also function in monitoring the recently envisioned treatment of KMT2B deficiency by inhibition of DNA methylation.

Cite

CITATION STYLE

APA

Mirza-Schreiber, N., Zech, M., Wilson, R., Brunet, T., Wagner, M., Jech, R., … Oexle, K. (2022). Blood DNA methylation provides an accurate biomarker of KMT2B-related dystonia and predicts onset. Brain, 145(2), 644–654. https://doi.org/10.1093/brain/awab360

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free