Mapping Neurologic Disease such as Multiple Sclerosis: How Whole-Genome Sequencing is Revolutionizing Diagnostics and Therapy

Neurologic diseases, including multiple sclerosis (MS), Alzheimer’s disease, and autism spectrum disorders, contribute substantially to the global burden of disability and mortality. Advances in genome sequencing technologies, particularly whole-genome sequencing (WGS), have paved the way for breakthroughs in understanding these complex disorders. A 2022 review by Xin Lin et al. in Neurology: Genetics highlights the potential of WGS to identify structural variations (SVs) that underpin many neurologic and neurodevelopmental diseases, improving diagnostics and offering new avenues for therapeutic interventions.

Structural Variations in Neurologic Diseases
SVs encompass large-scale genomic alterations, such as copy number variations (CNVs), transposable elements, and mosaic variations. These SVs contribute significantly to the unexplained genetic risk in many diseases:

Copy Number Variations (CNVs): These alterations involve deletions or duplications of DNA segments. For example, duplications of the PMP22 gene cause Charcot-Marie-Tooth disease, while deletions lead to hereditary neuropathy. In MS, CNVs in T-cell receptor genes have been associated with disease susceptibility.

Transposable Elements: Retrotransposons like LINE-1 and human endogenous retroviruses (HERVs) are mobile DNA sequences implicated in conditions such as MS and Parkinson’s disease.

Mosaic Structural Variations (mSVs): These post-zygotic mutations vary among cells. While their role in neurodegenerative diseases like Parkinson’s disease is emerging, more research is needed to understand their implications fully.

The Role of Whole-Genome Sequencing
WGS provides unparalleled insights by sequencing entire genomes, including non-coding regions, which are often overlooked by whole-exome sequencing (WES). WGS enables the detection of SVs that contribute to disease pathogenesis, such as:
De novo CNVs in early-onset Alzheimer’s disease.
Mosaic CNVs in autism spectrum disorders.
Retrotransposon insertions in neurologic conditions.

These findings underscore the utility of WGS in deciphering the complex genetic architecture of neurologic diseases.

Integrating RNA Sequencing and WGS
Combining RNA sequencing (RNA-seq) with WGS enhances the understanding of gene expression and splicing alterations caused by SVs. For example:
RNA-seq has clarified inconclusive genetic tests, diagnosing rare conditions like lissencephaly and intellectual disability.
Transcriptome-guided approaches facilitate the prioritization of SVs that affect gene expression, improving diagnostic accuracy.

Clinical Implications
The integration of WGS into clinical neurology has already demonstrated significant diagnostic improvements:
In a study of patients with intellectual disabilities, WGS achieved a diagnostic yield of 42%, compared to 27% with WES.
WGS detected pathogenic SVs missed by traditional methods, enabling earlier diagnosis and personalized treatment strategies.

These advancements herald a shift toward precision medicine, where genetic testing informs individualized care plans.

Challenges and Future Directions
Despite its promise, implementing WGS in routine clinical care faces hurdles:
Cost and Complexity: While sequencing costs are decreasing, data interpretation remains resource-intensive.
Knowledge Gaps: A comprehensive understanding of SVs’ roles in neurologic diseases is still developing.
Integration into Healthcare Systems: Standardized pipelines and clinician training are essential for widespread adoption.

Ongoing initiatives, such as the UK’s 100,000 Genomes Project and the Global Alliance for Genomics and Health, are addressing these challenges by building robust genomic databases and frameworks for clinical implementation.

Conclusion
The adoption of WGS marks a transformative moment in neurology. By uncovering the hidden genetic contributors to neurologic diseases, WGS not only enhances diagnostic accuracy but also opens doors to novel therapies and preventive strategies. As WGS technologies continue to evolve, their integration into healthcare systems will be pivotal in reducing the burden of neurologic diseases worldwide.

References:
Lin, X., Yang, Y., Melton, P. E., Singh, V., Simpson-Yap, S., Burdon, K. P., ... & Zhou, Y. (2022). Integrating genetic structural variations and whole-genome sequencing into clinical neurology. Neurology: Genetics, 8(4), e200005.