A way of examining multiple genes or the entire human genome at the same time, called next-generation sequencing (NGS), is a promising tool for diagnosing amyotrophic lateral sclerosis (ALS) in routine clinical practice, a review study suggests.
This method’s approach is faster and less expensive than the standard Sanger sequencing approach, and may provide important genetic information that furthers understanding of this complex disease.
But researchers are cautious with regard to routine use, as NGS frequently identifies genetic alterations whose significance is unknown, which may complicate genetic counseling for patients and people at risk.
Genetic alterations can include gene mutations, or changes in the DNA structure of a gene that can be passed to future generations, and epigenetic changes, or changes in gene expression, like being turned “on” to create a protein.
The study, “The NGS technology for the identification of genes associated with the ALS. A systematic review,” was published in the European Journal of Clinical Investigation.
While more than 20 different genes are implicated in the onset and development of familial and sporadic ALS, scientists are a long way from knowing all the genetic alterations involved in ALS.
This means that even patients with inherited forms of ALS often don’t known what gene is causing their disease, and thus have no way of knowing how it will evolve or how to best manage it.
The reason why most mutations are missed is because the traditional Sanger sequencing approach only examines known genes, which has raised the question of whether high-throughput NGS sequencing methods could be better at detecting disease-causing mutations in ALS patients.
Sanger sequencing is also slow, sequencing only a single DNA fragment at a time, while NGS sequences hundreds to thousands of genes at one time. NGS also is also a good tool for discovering unknown or rare genetic mutations associated with a condition, but it produces a huge amount of information. Its users must be knowledgeable to ably interpret its results.
Aiming to investigate if NGS is a reliable tool for diagnosing ALS, a team of Italian researchers examined data from published studies in ALS that evaluated NGS versus the traditional Sanger sequencing.
Their analysis included 14 studies, two of which directly compared the results of NGS and Sanger, and 12 whose NGS results were later validated using Sanger sequencing.
Overall, the studies included data from more than 2,300 patients, who were 18 to 87 years old at the time of diagnosis. Each study investigated one to 32 genes, with the most common – FUS, OPTN, SETX, VCP – being investigated in 11 studies.
Results showed that NGS usually identified more genetic variants associated with ALS than the Sanger method. A variant describes any alteration — benign or disease-causing — in the DNA sequences that compose a gene.
Across 13 studies (one study found no mutations with either method), NGS identified already known mutations in 21 genes, and new or rare variants in 27 genes. It also identified potentially disease-causing mutations, and variants of unknown significance in several patients.
These findings suggest that NGS is a promising tool for the diagnosis of ALS in routine clinical practice, being both faster and cheaper than traditional methods, and providing additional genetic information that helps in understanding the condition.
But researchers also noted its potential to detect variants or mutations whose significance to the disease course is unknown. Counseling patients and people at risk with these mutations would require a multidisciplinary team.
“NGS is a promising technology for the diagnosis of both familial and sporadic ALS, but the uncertainty concerning the interpretation of the results restricts its use in daily clinical practice,” the researchers wrote.
But “knowing the genetic profiles associated with ALS is essential to the better understanding of the disease and to identify new molecular and cellular pathways that can be potential markers and targets for new therapeutic interventions,” they added.
“Genetic testing will probably become important for the development of personalized genetic profiles, which combined with other related information, could bring towards a precision medicine for ALS patients.”
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