Adaptive sampling reveals pathogenic repeat expansion in spinocerebellar ataxia

Abstract

Autosomal dominant spinocerebellar ataxia type 4 (SCA4, MIM 600223) associated with axonal sensory neuropathy was originally described 28 years ago in a large Utah family of Swedish descent. Despite known linkage to chromosome 16q22.1, the pathogenic genetic variant remained elusive. We adopted targeted Oxford Nanopore Technologies long-read sequencing with adaptive sampling as a strategy to detect segregating structural variants within this 20 Mb genomic region without a priori assumptions or knowledge of variant features. Using this method, we identified a heterozygous (GGC)n repeat expansion in the last coding exon of the zinc finger homeobox 3 (ZFHX3) gene that segregates with disease. Five SCA4-afflicted individuals from two different families with Swedish ancestry were found to have 48–57 GGC repeats, whereas non-expanded alleles and unaffected spouses had 21 repeats with non-specific ‘A’ interruptions. This study showcases the use of long-read sequencing with adaptive sampling to investigate unsolved genetic disorders.

Biography

Claire Anderson did an undergraduate degree in biomedical science and went on to specialise in developmental biology during her postgraduate studies and post-doctoral work. Claire is now a research assistant in the lab of Professor Mina Ryten — funded by The Michael J. Fox Foundation for Parkinson’s Research and Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network initiative. Claire uses long-read sequencing technologies to understand the pathological mechanisms of Parkinson’s disease and other neurodegenerative disorders.