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Expert Panel Publishes Guidelines for Genetic Testing, Counseling in ALS

NEW YORK – An expert panel led by researchers at the Ohio State University Wexner Medical Center and College of Medicine has published a set of evidence-based guidelines for genetic testing and counseling for people with amyotrophic lateral sclerosis (ALS).

The guidelines consist of 35 statements, whose recommendations regarding test methods and reporting establish a framework for clinicians to offer genetic testing and detail the information that should be provided to patients. They were published last week in the Annals of Clinical and Translational Neurology.

ALS is a neurodegenerative disease that primarily affects motor neurons, causing progressive loss of voluntary limb control and difficulty breathing.

The researchers reviewed available literature as well as lab practices, which they said revealed a lack of methodological consistency and clinical result reporting. It also revealed sparse published evidence for result interpretation and reporting.

Each recommendation was scored based on the strength of the underlying evidence, for which the authors used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, which is considered the gold standard for assessing evidence in medicine and relies on randomized control trials (RCTs). Additionally, they applied the Evaluation of Genomic Applications in Practice and Prevention (EGAPP), which helped to evaluate evidence where RCT data was sparse.

The primary recommendation contained in the guidelines is that all persons with ALS should be offered genetic testing.

The yield of genetic testing is sufficiently high, the authors wrote, to lead to therapeutic intervention in some people, and individuals with ALS generally want access to genetic testing and see benefits from obtaining it, regardless of family history or test outcome.

Pathogenic or likely pathogenic gene variants may be found in the majority of familial ALS cases and in a minority of apparently sporadic cases among people of European ancestry. Although the frequencies of known ALS variants appear lower in other populations, less data has been collected on people of non-European ancestry.

The guidelines strongly recommend that gene panels used for testing include the genes C9orf72, SOD1, FUS, and TARDBP; and that additional genetic testing should include genes that ClinGen has determined to be strongly and definitively associated with ALS.

Additionally, the group recommends that if a US Food and Drug Administration-approved gene-targeted therapy becomes available, all persons with ALS should be offered testing for that gene.

Guidelines covering genetic counseling included recommendations that prior to testing, all people with ALS should be provided with genetic counseling and education, which should include discussions of inheritance patterns and penetrance.

Post-test, the group advises that clinicians and counselors help their ALS patients to understand that a negative genetic test result does not exclude genetic forms of ALS, that variants of unknown significance may or may not contribute to a person's condition, and that the interpretation of a person's test results may change over time.

Providers are further advised to develop a family pedigree going back at least three generations.

Recommendations for laboratory methods and reporting largely focused on methods and criteria for testing C9orf72 repeat expansion, which is the most common genetic cause of ALS and related disorders.

Finally, reporting guidelines included the recommendations that ALS gene panel reports should clearly differentiate between genes that are causal for ALS and those genes where the evidence is sparse, conflicting, or insufficient, based on ClinGen classifications; that reports should highlight gene regions that were inadequately assessed via targeted-capture, whole-exome, or whole-genome methods; and that these regions be further interrogated later.

"These guidelines reflect current genomic technology, which will evolve along with our scientific understanding of the genetics of ALS," corresponding author Jennifer Roggenbuck, a licensed genetic counselor and associate professor in the Division of Human Genetics at the Wexner Medical Center, said in a statement.

"It is expected that genetic associations with ALS and related disorders will continue to expand, and with it, the complexity of results that must be communicated," she added. "We view these guidelines as a first step toward a uniform and equitable approach to ALS genetic testing that will require revision periodically as new genetic discoveries and new genetic therapies move forward for people living with ALS."