Potential of Whole Genome Sequencing in Diagnosing Neurological Repeat Expansion Disorders

Repeat expansion disorders (REDs) are a group of genetically complex and clinically heterogeneous conditions caused by expansions of short tandem DNA sequences. These disorders affect approximately 1 in 3,000 individuals and include diseases such as Huntington’s disease and fragile X syndrome. Historically, diagnosing REDs has relied on locus-specific tests, such as PCR and Southern blotting, which can be limited by their targeted nature and the overlapping symptoms of REDs with other neurological conditions.

A recent study published in The Lancet Neurology (2022) by Ibañez et al. evaluated the use of whole genome sequencing (WGS) as a diagnostic tool for REDs. This landmark research aims to address the diagnostic gap for patients with undiagnosed neurological conditions.

Key Findings: WGS Shows High Sensitivity and Specificity
The study retrospectively assessed the diagnostic accuracy of WGS across 13 RED-associated loci, comparing it with PCR results from 793 tests performed within the UK National Health Service (NHS). WGS demonstrated a sensitivity of 97.3% and specificity of 99.6% in identifying expanded alleles, which improved further after visual inspection of sequence data.

In a prospective clinical validation using data from 11,631 patients in the 100,000 Genomes Project, WGS identified 68 cases of pathogenic repeat expansions, including some previously undiagnosed patients. These results underline WGS's robustness as a first-line diagnostic tool.

The Clinical Impact: Expanding Diagnostic Capabilities
WGS successfully identified expansions in genes like C9orf72 (linked to ALS and frontotemporal dementia) and HTT (Huntington’s disease), even in cases with atypical presentations or pediatric onset. Importantly, the study revealed that some repeat expansions, such as those in FMR1, could be misclassified due to underestimation of repeat size by WGS. However, these issues were mitigated through confirmatory PCR testing and refined bioinformatic algorithms.

Advancing Precision Medicine
The findings suggest that integrating WGS into routine clinical diagnostics could revolutionize care for RED patients. By replacing sequential, locus-specific testing with a comprehensive, high-throughput approach, WGS offers:
Efficiency: Simultaneous testing of multiple loci.
Accuracy: Reduced false negatives and detection of atypical cases.
Cost-effectiveness: Potentially lowering costs associated with multiple targeted tests.

Technological Limitations and Future Directions
While WGS is a promising tool, its limitations in accurately sizing large expansions (e.g., >200 repeats in FMR1) indicate the need for complementary methods like long-read sequencing. Additionally, advancements in bioinformatics, such as enhanced algorithms for detecting complex repeat structures, will further bolster its diagnostic utility.

Implications for Clinical Practice
The implementation of WGS aligns with global efforts to integrate genomic medicine into healthcare. In the UK, it is already included in the NHS Genomic Test Directory for undiagnosed neurological diseases, emphasizing its clinical relevance.

Conclusion: Transforming Diagnosis for Neurological Disorders
This study highlights WGS as a transformative tool for diagnosing REDs, offering hope for many undiagnosed patients. As genomic technologies advance, WGS could become the cornerstone of precision medicine for rare neurological disorders, enabling timely interventions and improved outcomes.

References:
Ibañez, K., Polke, J., Hagelstrom, R. T., Dolzhenko, E., Pasko, D., Thomas, E. R. A., ... & Zarowiecki, M. (2022). Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study. The Lancet Neurology, 21(3), 234-245.