Whole-genome Sequencing Provides ALS Genetic Architecture ‘Snapshot’

Disease-associated mutations were seen in more than 25% of 1,000 patients studied

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Whole-genome sequencing, a type of genetic screening that examines a person’s complete DNA sequence, may be a promising way to identify disease-causing mutations in people with amyotrophic lateral sclerosis (ALS), according to a study of Italian patients.

Disease-associated mutations were found in more than a quarter of 1,043 Italian ALS patients screened. Based on these findings, many patients would be eligible for gene-based therapies, researchers noted.

“We show that whole-genome sequencing increases diagnostic yield and facilitates the assessment of the pathogenic [disease-causing] role of involved genes,” the researchers wrote. “This information will be crucial for clinical care as precision therapeutics emerge as effective treatments. In anticipation of that, we consider whole-genome sequencing as the first-tier genetic test on all ALS patients.”

The study, “Systematic evaluation of genetic mutations in ALS: a population-based study,” was published in the Journal of Neurology, Neurosurgery & Psychiatry. 

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The exact cause of ALS is not fully understood, but environmental, lifestyle, and genetic factors are all thought to play a role. Mutations in more than 30 genes have been linked with ALS. Some are known to directly cause disease, whereas others indirectly influence a person’s susceptibility to ALS.

While knowing which genetic factors contribute to disease in each patient could help tailor treatment approaches, the true prevalence of ALS mutations remains unknown.

Researchers in Italy, along with colleagues at the U.S. National Institute on Aging, conducted a genetic sequencing analysis in a group of ALS patients. Their goal was to form “a snapshot of what we currently know about the genetic architecture of ALS,” the team wrote.

The study included 1,043 ALS patients who had been enrolled in the Piemonte and Valle d’Aosta Register for ALS (PARALS). Another 755 healthy volunteers were also included and used as controls.

Whole-genome sequencing was used to perform the genetic screen. This technique involves screening all the DNA in a person’s entire genetic sequence, including regions of DNA that directly code for proteins as well as non-coding, or regulatory, regions.

After sequencing the DNA, the team examined the genetic sequence of 46 genes previously implicated in ALS. The results retrieved 96 disease-causing mutations in 203 patients and mutations deemed potentially disease-causing were identified in another 76. Overall, more than a quarter of patients (26.9%) had a disease-causing mutation, the researchers noted.

The most common mutations were in the C9orf72 gene (7.7%), followed by the genes SOD1 (2%), NEK1 (1.8%), TARDP (1.4%), and KIF5A (0.8%).

Disease-causing mutations were found in most people with familial ALS (75.2%), and in 21.5% of people with sporadic ALS – not associated with a family history of the disease.

Mutations also were more commonly identified in those with early-onset ALS (43.9%), whose disease started before age 50. Among those with late-onset disease, whose age at first symptoms was greater than 75 years, only 19.7% had disease-causing mutations. About half of them were in C9orf72.

The team also found one gene considered a high-risk genetic factor for ALS. Mutations in this gene, called ATXN2, were found in 3.9% of all patients and increased the likelihood of developing ALS by nearly threefold.

Most patients had only one disease-causing mutation, with only 1.3% showing more than one. According to the researchers, this low percentage contrasts with previous hypotheses that ALS was oligogenic, or caused by interactions between multiple genetic factors.

They noted, however, that “future discovery of more genes involved in ALS pathogenesis [disease mechanisms] may reveal true oligogenicity.”

The team also noted that considering that gene-targeting therapies are in development for multiple of the studied genes, at least 144 people (13.8%) in the study could be eligible for gene-based ALS therapies.

Ultimately, the findings “support the use of whole-genome sequencing in ALS patients at the time of their diagnosis, irrespective of family history, age at onset or clinical phenotype.”