Utilizing nanopore long-read sequencing to simplify hereditary movement disorder diagnostics

Biography

Dr Paula Saffi-Awad is an MD, PhD, and movement disorders neurologist specializing in hereditary neurodegenerative diseases since 2016. Her recent research focuses on Parkinson's disease genetics, exploring both monogenic and polygenic contributions. She is dedicated to simplifying the diagnostic journey for patients with rare diseases in Chile through innovative, cost-effective, and accessible genetic approaches. With expertise spanning from DNA extraction to bioinformatics, her work aims to bridge gaps in diagnosis and improve outcomes for underrepresented populations.

Abstract

The diagnostic journey for hereditary movement disorders is often lengthy, expensive, and inconclusive, relying on short-read technologies such as PCR, gene panels, whole-exome sequencing, and whole-genome sequencing (WGS). While these methods vary in cost and scope, they fail to comprehensively detect all classes of genetic variants, resulting in suboptimal diagnostic rates.

Addressing these gaps, long-read sequencing with nanopore technology offers a transformative approach capable of uncovering the full spectrum of genetic alterations across diverse clinical scenarios. We conducted a pilot study on 13 individuals with suspected hereditary movement disorders, including two families (each with two affected members) and nine index cases presenting with ataxia, ataxia-parkinsonism, parkinsonism, or atypical parkinsonism phenotypes.

Using nanopore WGS (average N50 = 21 kb, 130 Gb per flow cell), we identified the recently described spinocerebellar ataxia type 4 (SCA4)-related expansions in ZFHX3 (four individuals), as well as single nucleotide variant (SNV) pathogenic variants in GBA1 (p.Asn409Ser, two patients) and LRRK2 (p.G2019S, two patients). Notably, our diagnostic yield reached 80% for ataxia and 50% for parkinsonism, surpassing previous reports and providing definitive answers for cases with prior negative genetic studies.

This successful pilot demonstrates the potential of nanopore sequencing to revolutionise genetic testing for hereditary movement disorders. Its ability to comprehensively detect diverse variants, coupled with the scalability and cost efficiency of adaptive sampling, represents a paradigm shift in diagnostics. Building on these findings, we are now expanding our analysis to larger cohorts to validate and extend its clinical utility.