Genetic Testing for ALS: What Every Patient and Family Should Know

Receiving a diagnosis of Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, can be overwhelming. It's a complex and progressive neurological disease that affects nerve cells in the brain and spinal cord, leading to loss of muscle control. While the journey with ALS varies for each person, understanding the potential role of genetics is becoming an increasingly important part of managing the condition.

Genetic testing for ALS is no longer just for families with a strong history of the disease. Significant advances in understanding the genetic underpinnings of ALS mean that genetic testing is now recommended for most, if not all, individuals diagnosed with ALS. This information can provide valuable insights for patients and their families, influencing everything from understanding the disease to potential treatment options.

Why is Genetic Testing Important in ALS Today?

Genetic testing for ALS helps answer crucial questions and provides several benefits:

• Understanding the Cause: For some people, a specific genetic change is the primary cause of their ALS. Identifying this can provide clarity and help families understand the inheritance patterns if there is a family history.
• Informing Prognosis: While ALS progression varies, certain genetic variants may be associated with faster or slower disease courses, potentially helping manage expectations and plan care (Grassano et al., 2022).
• Eligibility for Clinical Trials: Many new and promising therapies being developed for ALS are designed to target specific genetic causes. Knowing your genetic profile can make you eligible for clinical trials testing these targeted treatments (Benatar et al., 2022; Chia et al., 2018).
• Potential for Personalized Medicine: As our understanding grows, genetic information is paving the way for more personalized treatment approaches tailored to an individual's specific genetic makeup (Morgan et al., 2018; Tzeplaeff etal., 2023).
• Informing Family Members: Identifying a specific genetic cause can provide valuable information for family members who may wish to understand their own potential risk, though this involves careful consideration and genetic counseling (Benatar et al., 2016).

As noted in supporting information, systematic genetic screening reveals a clinically reportable pathogenic variant in 21% of ALS patients and variants of uncertain significance in another 21%. This highlights that genetic factors are present in a significant portion of individuals with ALS, even those without a known family history. Genetic profiling is becoming standard practice and helps guide therapy development.

Familial vs. Sporadic ALS: The Role of Genetics in Both

Historically, ALS was often categorized as either "familial" (fALS), when there was a clear family history, or "sporadic" (sALS), when there wasn't. While this distinction is still used, genetic discoveries have blurred the lines.

• Familial ALS (fALS): Accounts for about 10-15% of cases. In these families, a specific genetic mutation is often passed down from generation to generation (Masrori & Van Damme, 2020).
• Sporadic ALS (sALS): Accounts for about 90% of cases. However, even in sALS, genetic factors can play a significant role. Studies show that a notable percentage of individuals with sALS still carry genetic variants known to cause or increase the risk of ALS (Grassano et al., 2022).

This is why genetic testing is now recommended for all individuals with an ALS diagnosis, regardless of family history (Roggenbuck et al., 2023).

What Genes Are Tested for in ALS?

Thanks to extensive research, over 40 genes have been associated with ALS risk or causation (Wang et al., 2023). While comprehensive testing panels look at many genes, some of the most common ones include:

• C9orf72: This is the most common genetic cause of ALS, particularly in familial cases (30-50%), but it's also found in a significant portion of sporadic cases (around 7%) (Masrori & Van Damme, 2020). Expansions in this gene are also linked to frontotemporal dementia (FTD), highlighting the overlap between these conditions (Masrori & Van Damme, 2020).
• SOD1: This was the first gene identified as a cause of ALS and is particularly relevant as it is the target of some of the most advanced gene-targeted therapies currently being studied (Benatar et al., 2022; Picher-Martel et al., 2016).
• TARDBP: This gene codes for a protein called TDP-43, which is found in abnormal clumps in the motor neurons of most people with ALS, regardless of the underlying cause (Meyer, 2021). Mutations in the TARDBP gene itself are a known cause of the disease.
• FUS: Similar to TARDBP, mutations in the FUS gene, which codes for another RNA-binding protein, are also a cause of ALS.

Current guidelines recommend testing for at least these four genes (C9orf72, SOD1, FUS, and TARDBP) as a minimum for all individuals diagnosed with ALS (Roggenbuck et al., 2023). More comprehensive panels using technologies like Whole Genome Sequencing (WGS) can screen dozens of known ALS-related genes and may offer a higher diagnostic yield (Grassano et al., 2022).

What to Expect from ALS Genetic Testing

Genetic testing for ALS typically involves a simple blood or saliva sample. This sample is sent to a specialized laboratory that analyzes your DNA.

The process usually includes:

1. Pre-Test Counseling: Before testing, a genetic counselor or neurologist will discuss the reasons for testing, the genes being analyzed, the potential results (positive, negative, or variant of uncertain significance), and the implications of each result for you and your family. This is a crucial step to ensure you fully understand the process and potential outcomes.
2. The Test: A blood or saliva sample is collected.
3. Laboratory Analysis: The lab sequences the relevant genes to look for specific changes or mutations known to be associated with ALS.
4. Post-Test Counseling: Once the results are ready, the genetic counselor or neurologist will explain the findings in detail.
   • Positive Result: Means a pathogenic (disease-causing) variant was found. The counselor will discuss what this specific variant means, potential implications for prognosis, eligibility for trials, and options for family members.
   • Negative Result: Means no known pathogenic variants were found in the genes tested. It's important to understand this does not rule out a genetic cause entirely, as there may be other genes not yet discovered or included on the panel, or other genetic mechanisms at play.
   • Variant of Uncertain Significance (VUS): Means a genetic change was found, but it's not currently known if this change causes ALS. This can be the most challenging result, and often requires more research over time to clarify its significance.

Testing Family Members: A Separate Conversation

If a specific genetic cause is identified in a person with ALS, family members (like siblings, children, or parents) may be at increased risk of carrying the same variant. However, deciding whether to pursue genetic testing when you don't have symptoms (presymptomatic testing) is a deeply personal and complex decision.

Expert panels have developed guidelines specifically for presymptomatic testing and counseling (Benatar et al., 2016). This testing is not routinely offered and requires extensive pre-decision and pre-test counseling to ensure individuals fully understand the potential emotional, social, and financial implications of learning they are at increased risk for a serious, currently incurable disease. It's a process that should be undertaken with careful consideration and professional support.

The Future: Genetics and Personalized ALS Care

Genetic research is rapidly transforming our understanding of ALS. Identifying specific genetic causes is unlocking new pathways for developing targeted therapies that address the root cause of the disease in individuals with those mutations (Chia et al., 2018). Clinical trials for these gene-targeted therapies, like those for SOD1-ALS, represent a significant step towards personalized medicine in ALS care (Benatar et al., 2022).

As genetic testing becomes more widespread and affordable, and as research continues to uncover new genes and understand their functions, genetic information will play an even more central role in diagnosing, predicting the course of, and treating ALS.

Conclusion

Genetic testing for ALS is a valuable tool that can provide important information for patients and their families. It's a key step in understanding the disease, potentially accessing targeted treatments through clinical trials, and planning for the future. While the results can sometimes be complex, comprehensive genetic counseling is available to guide you through the process.

If you or a loved one has been diagnosed with ALS, discuss genetic testing options with your neurologist or an ALS specialist. They can help you understand if testing is right for you and connect you with genetic counseling services.

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References

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