Revolutionizing Neurogenetics: The Role of Next-Generation Sequencing in Decoding Complex Disorders

Neurogenetic disorders, a group of conditions with diverse genetic etiologies, have long puzzled researchers and clinicians due to their complex pathogenesis. The advent of Next-Generation Sequencing (NGS) technologies has significantly advanced our ability to decode these disorders. This review, authored by Hui Sun and colleagues, delves into the transformative role of NGS in unraveling the genetic underpinnings of neurogenetic diseases, such as Charcot–Marie–Tooth disease (CMT), spinocerebellar ataxias (SCAs), epilepsy, and multiple sclerosis (MS). Here, we summarize its core insights and implications for clinical practice.

Key NGS Modalities in Neurogenetic Research
NGS encompasses several approaches, each tailored to specific diagnostic and research needs:
Whole-Exome Sequencing (WES): By focusing on protein-coding regions, WES has identified pivotal mutations linked to conditions like amyotrophic lateral sclerosis (ALS), with its cost-efficiency making it a preferred diagnostic tool.

Whole-Genome Sequencing (WGS): Offering comprehensive genome coverage, WGS excels in detecting noncoding variants, structural variations, and de novo mutations, surpassing WES in diagnostic yield for conditions such as mitochondrial diseases.

Gene Panels: Targeted sequencing of predefined gene sets provides a high diagnostic rate for disorders with known genetic heterogeneity, such as CMT and muscular dystrophies.

Applications in Specific Neurogenetic Diseases
Charcot–Marie–Tooth Disease (CMT):
Over 100 genes are implicated in CMT, with mutations often influenced by genetic drift and founder effects. NGS has enabled the discovery of rare variants in genes like MORC2 and IGHMBP2, highlighting the potential for tailored therapies based on mitochondrial and cytoskeletal pathologies. Spinocerebellar Ataxias (SCAs):
SCAs exhibit both repeat expansions and nonrepeat mutations. NGS has unveiled novel variants in genes such as CACNA1A and STUB1, underscoring its utility in diagnosing complex phenotypes. Founder effects influence subtype prevalence, with regional variations in SCA types reflecting unique genetic ancestries. Epilepsy:
NGS has illuminated the genetic basis of epilepsy, identifying mutations in ion-channel genes like KCNA2 and GABRG2. These discoveries inform personalized treatment strategies and enhance understanding of drug response mechanisms.

Multiple Sclerosis (MS):
Research into HLA gene variants has positioned NGS as a tool for identifying biomarkers and exploring the genetic complexity of MS. Despite the complex genetic etiology of MS, NGS-based studies in multi-incident MS families have shown the presence of shared genetic risk factors, although individual disease-causing mutations remain elusive. This reinforces the polygenic and multigenic nature of MS, where a combination of common and rare variants collectively contribute to disease susceptibility.

Challenges in Interpretation and Limitations
Variants of Uncertain Significance (VUS): The ambiguous nature of many genetic findings poses challenges for clinical decision-making. Advanced computational tools and long-read sequencing technologies are pivotal in addressing these uncertainties.

De Novo Mutations (DNMs): DNMs play a significant role in sporadic cases of adult-onset neurodegenerative disorders. Trio-based sequencing is enhancing the identification of novel pathogenic variants.

Future Directions and Impact
The review emphasizes that NGS, complemented by emerging third-generation sequencing technologies like single-molecule real-time (SMRT) sequencing, holds promise for decoding the intricate molecular mechanisms of neurogenetic diseases. By bridging the gap between research and clinical application, NGS is paving the way for precision medicine, from early diagnosis to targeted interventions.

Conclusion: A Paradigm Shift in Neurology
Next-Generation Sequencing is revolutionizing the diagnosis and management of neurogenetic disorders. As its integration into clinical practice deepens, the potential to improve patient outcomes and understand rare genetic diseases becomes increasingly attainable. Continued advancements in sequencing technologies and data interpretation tools will undoubtedly expand the horizons of neurogenetics.

References:
Sun, H., Shen, X. R., Fang, Z. B., Jiang, Z. Z., Wei, X. J., Wang, Z. Y., & Yu, X. F. (2021). Next-generation sequencing technologies and neurogenetic diseases. Life, 11(4), 361.