#AANAM – Genetic Testing Recommended for All ALS Patients

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Editor’s note: The ALS News Today team is providing in-depth coverage of the 2021 Virtual AAN Annual Meeting, April 17–22. Go here to read the latest stories from the conference.

More than one-quarter of amyotrophic lateral sclerosis (ALS) patients — with or without a family history of ALS — have mutations in genes associated with the disease, according to a study of about 1,000 patients in Italy.

These findings add to the growing body of evidence highlighting that ALS-linked mutations and risk factors in both familial and sporadic ALS patients are more common than previously thought.

As such, the researchers recommend that genetic testing be offered to all ALS patients, regardless of family history, for diagnostic and prognostic purposes.

The study’s results were presented by Adriano Chiò, MD, the director of University of Torino’s ALS Center, in Italy, in an oral presentation, titled “Clinical Utility of Whole-Genome Sequencing in an ALS Cohort,” at the 2021 virtual American Academy of Neurology Annual Meeting, held April 17–22.

Most ALS cases are considered sporadic, but 5%–10% have been shown to be familial, or inherited — with the most commonly mutated genes being C9ORF72SOD1TARDBP, and FUS.

However, “the true proportion of cases that can be attributed to genetic factors remains unclear,” the researchers wrote, as only people with a history of ALS or dementia in their family, or who experience disease onset at young ages, are routinely offered genetic screening.

In addition, the role of genome-wide screening, or genetic testing that searches for mutations in all of a person’s genetic material, in clinical practice “is still undetermined,” the team added.

Researchers at Torino’s ALS Center in collaboration with those at the National Institute of Aging, in the U.S., have now evaluated the frequency and spectrum of mutations in 45 ALS-related genes in 1,043 familial and sporadic ALS patients from an Italian ALS registry and 747 healthy individuals.

They did so through whole-exome sequencing, a widely used next-generation sequencing (NGS) method that looks for mutations in all of a person’s exons — the sections of genetic information needed to make proteins — through a blood sample.

NGS, which was previously pointed out as a promising tool for ALS diagnosis in routine clinical practice, is a type of DNA testing that allows the identification of mutations in multiple genes or the entire human genome at the same time.

Participants’ blood samples were also screened for the presence of ALS-related mutations that involve an abnormal expansion of specific sections of a gene, both through whole-exome sequencing and a standard method that analyzes only a single DNA fragment or gene at a time.

Results showed that 212 known or potentially disease-causing mutations, including 60 new mutations, were identified in 297 (28.5%) ALS patients, and that 11.4% of patients carried ALS-associated DNA expansions.

Particularly, 79 (7.6%) patients had long expansions in the C9ORF72 gene, which are known to cause some cases of familial ALS, while intermediate expansions in the ATXN2 gene, which were previously shown to increase ALS risk and to be associated with some sporadic ALS cases, were found in 40 (3.8%) patients.

ATXN2 is considered an ALS genetic modifier, meaning that while variants in this gene do not cause the disease themselves, they can influence the frequency and severity of disease symptoms. Expansions in this gene were also found in eight (1.1%) healthy individuals, Chiò noted.

In addition, 121 patients (11.6%) carried a common ALS-related mutation in the UCN13A gene, called rs12608932 A>C.

Notably, 32 patients (3.1%) had more than one mutation, usually one in a major ALS-related gene and another in a “more rare or uncommon gene,” Chiò said.

“We detected likely causal variants in 28.5% of our [patient group] and 3% of patients carried multiple potential [disease-causing] mutations,” Chiò said, adding that 3.8% had a known ALS genetic risk factor (ATXN2 intermediate expansions).

The data also demonstrated that whole-exome sequencing “has a high sensitivity in detecting clinically relevant [DNA] expansions,” with a 100% agreement with traditional methodology, he added.

“We conclusively show that genetic mutations and risk factors in both familial and sporadic ALS patients are more common than previously thought, thus highlighting that genetics play a central role in ALS [development],” the researchers wrote.

The study also highlights that this type of genetic screening “can have a significant impact on patients’ diagnosis, management, and genetic counselling,” in addition to allowing periodic re-analysis as new ALS mutations are uncovered, Chiò said.

“I think that we need to do [genetic testing] on all ALS patients,” Chiò concluded.