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Updated: Aug 5, 2026
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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Long-read sequencing for neurological disorders: opportunities, challenges, and future directions
Hanabi Geiger1, Yutaka Furuta2, B Lakshitha A Perera3
1Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. hanabi.u.geiger@vanderbilt.edu.
Summary
Long-read sequencing (LRS) improves genetic diagnosis for neurological disorders (NDs) by detecting complex variants missed by short-read sequencing (SRS). Overcoming technical and cost barriers is crucial for widespread clinical use of LRS in diagnosing NDs.
Area of Science:
- Genomics
- Neurology
- Medical Diagnostics
Background:
- Neurological disorders (NDs) often have genetic origins, but traditional diagnostic methods capture only downstream effects.
- Short-read sequencing (SRS) has limitations in detecting repeat expansions, structural variants, and other complex genetic alterations common in NDs.
- Significant gaps exist in diagnosing NDs due to the inability of current sequencing technologies to resolve complex genetic variations.
Purpose of the Study:
- To review the capabilities of long-read sequencing (LRS) technologies for diagnosing genetic neurological disorders.
- To evaluate existing studies that utilize LRS for genetic diagnosis in NDs.
- To assess the technological, analytical, cost, and ethical barriers hindering the clinical adoption of LRS.
Main Methods:
- Comprehensive literature review of studies employing long-read sequencing (LRS) for genetic diagnosis in neurological disorders (NDs).
- Evaluation of LRS capabilities in detecting variant types difficult for short-read sequencing (SRS).
- Assessment of current challenges to clinical implementation, including technological, analytical, financial, and ethical factors.
Main Results:
- Long-read sequencing (LRS) enables the detection of complex genetic variants, including large repeat expansions and structural variants, often missed by SRS.
- LRS has shown promise in diagnosing conditions like Duchenne muscular dystrophy, fragile X syndrome, spinocerebellar ataxias, and mitochondrial disorders.
- Key challenges remain, including the need for high-quality DNA, sophisticated analytical pipelines, high costs, and ethical considerations regarding equity and incidental findings.
Conclusions:
- Long-read sequencing (LRS) offers significant advantages for identifying complex genomic contributors to neurological disorders, potentially increasing diagnostic yield.
- Widespread clinical implementation of LRS is contingent upon overcoming substantial technical, logistical, and ethical hurdles.
- This review provides guidance for clinicians and researchers on the current applications and future requirements for adopting LRS in ND diagnostics.
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