Functional characterization of variants of unknown significance in a spinocerebellar ataxia patient using an unsupervised machine learning pipeline

Abstract

Neurodegenerative disease: Finding new mutations associated with ataxia Two genetic mutations combine to cause a novel variant of spinocerebellar ataxia (SCA), a rare neurodegenerative disease. SCA affects the cerebellum, a brain region that controls movement, causing progressive coordination problems. Presented with a patient with an atypical form of SCA, Ray Truant at McMaster University in Hamilton, Canada, and co-workers used whole-genome sequencing to identify mutations in two genes: ATXN7, involved in cytoskeleton maintenance, and TOP1MT, in mitochondria, the cellular powerhouses. Unable to see differences in the affected tissues using routine microscopy, the researchers used computer-guided microscopy image analysis to determine that the altered ATXN7 protein was mis-located in cells. High-fidelity measurements of cell metabolism showed that mitochondria with altered TOP1MT produced insufficient energy. These results clarify the genetics of ataxia, and offer new ways to identify the effects of rare mutations.