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An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics


BACKGROUND: Short tandem repeat (STR) expansion disorders are an important cause of human neurological disease. They have an established role in more than 40 different phenotypes including the myotonic dystrophies, Fragile X syndrome, Huntington's disease, the hereditary cerebellar ataxias, amyotrophic lateral sclerosis and frontotemporal dementia. MAIN BODY: STR expansions are difficult to detect and may explain unsolved diseases, as highlighted by recent findings including: the discovery of a biallelic intronic 'AAGGG' repeat in RFC1 as the cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS); and the finding of 'CGG' repeat expansions in NOTCH2NLC as the cause of neuronal intranuclear inclusion disease and a range of clinical phenotypes. However, established laboratory techniques for diagnosis of repeat expansions (repeat-primed PCR and Southern blot) are cumbersome, low-throughput and poorly suited to parallel analysis of multiple gene regions. While next generation sequencing (NGS) has been increasingly used, established short-read NGS platforms (e.g., Illumina) are unable to genotype large and/or complex repeat expansions. Long-read sequencing platforms recently developed by Oxford Nanopore Technology and Pacific Biosciences promise to overcome these limitations to deliver enhanced diagnosis of repeat expansion disorders in a rapid and cost-effective fashion. CONCLUSION: We anticipate that long-read sequencing will rapidly transform the detection of short tandem repeat expansion disorders for both clinical diagnosis and gene discovery.

Type Journal
ISBN 2051-5960 (Electronic) 2051-5960 (Linking)
Authors Chintalaphani, S. R.; Pineda, S. S.; Deveson, I. W.; Kumar, K. R.
Publisher Name Acta Neuropathologica Communications
Published Date 2021-05-31
Published Volume 9
Published Issue 1
Published Pages 98
Status Published in-print
DOI 10.1186/s40478-021-01201-x
URL link to publisher's version