ALS Canada Gene Hub

What is the Gene Hub and how do I use it?

The ALS Society of Canada (ALS Canada) is committed to a future where anyone living with ALS, or with a known genetic risk of ALS, understands how genetics may impact them. We aim to provide accurate and relevant information, as well as pathways to action for those who wish to access genetic care.

This will be a multi-pronged approach that involves:

  • working with experts across the country to support the evolution of genetic counselling and testing practices;
  • attracting top genetically-targeted experimental and proven treatments to Canada;
  • exploring opportunities for individuals with high genetic risk for ALS to contribute to research, and work towards better care; and
  • support for people with high genetic risk for ALS in line with best practices being developed through global initiatives.

The ALS Canada Gene Hub is intended to serve as a central resource for global ALS genetic information and opportunities. The Gene Hub provides an overview of how genetics work, to information and resources on genetic counselling and testing – where you go within the Gene Hub can depend on your level of understanding of genetics and what kind of information you’re looking for.

If you already have the basics covered, please explore the rest of the links as needed. We welcome suggestions on how to improve this content and invite you to share your thoughts with us via research@oldals.thedev.ca.

Note: The information contained in the ALS Canada Gene Hub is for educational and informational purposes only. It is not intended to replace the importance of speaking with an ALS neurologist and/or genetic counsellor.

1. The basics of genetics

1.1 Introduction to Genetics

We recommend starting with this section if you are new to the world of genetics.

What are genes?

Humans are made up of cells, which are the building blocks of our organs and body. Inside each cell, we have a DNA sequence. This sequence is the blueprint needed to build and maintain a human being. This DNA sequence is made up of individual DNA bases. A specific section of DNA bases is known as a gene, which defines our traits and characteristics.

Genes can be passed on from parent to child, resulting in family members having similar features. Genes carry instructions for how to produce things our body needs, such as proteins. Proteins are building blocks for cells, and what our body uses for normal functioning.

What are variants (mutations)?

Sometimes, due to internal issues while replicating our DNA or external factors, we can have errors in our DNA sequence. These errors happen all the time, in every person. While our bodies have mechanisms to fix these errors, sometimes corrections are not possible, leading to permanent variations in our genes.

A genetic variant is an alteration in the normal sequence of a gene. Normally, a DNA base is altered, missing, or added. Usually these variants are benign, but sometimes they can be pathogenic.

Pathogenic variants can change the instructions for protein production. Proteins produced from these altered genes might not function the way they are supposed to, or the body might not be able to produce them at all. This can alter normal bodily functions, and potentially lead to disease.

Genetic code errors are frequently referred to as “mutations.” This site will use the term “variant” where possible, which means the same thing.

RECIPE BOOK ANALOGY

Let’s look at genes with a recipe book analogy: If the cell is our kitchen, the DNA sequence inside our cells is a cookbook. Each gene is a specific recipe inside of it, and the resulting protein is the resulting dish created.

If we change any of the instructions on the recipe page (erase an ingredient, or change its quantities), the dish will be different.

Some of these changes can be harmless, for example, swapping chocolate for vanilla when making a cake. However, if we don’t include the flour, the cake will fall apart.

Similarly, proteins created from some genetic variants can result in a defective protein or the protein not being created at all.

What are hereditary variants?

Gene variants that are inherited from your parents are called hereditary. Not every variant the parent has will be passed on to their children, as this depends on the gene and genetic pattern of inheritance.

You can also develop new variants throughout your life, called acquired variants, and there is little to no risk of passing these genes on to your children.

What is a family history and familial ALS (FALS)?

While researchers are still working to understand the exact causes of ALS, it is known that some cases are caused by a genetic variant.

Several genes have been identified that when altered, can contribute to disease. Approximately five to ten percent of people living with ALS will have a family history of the disease. A family history means multiple family members were affected by the disease, due to a hereditary variant in a gene related to ALS.

This is traditionally termed “familial” ALS (FALS), and in some cases, there may be a shared history of frontotemporal dementia (FTD). For some genes, the relation to FTD is stronger.*

*ALS Canada is working to provide better information and understanding on the ALS & FTD spectrum to better support this community. In the meantime, for more information, please check the resources AFTD: ALS and Frontotemporal Degeneration and the ALS Association: What Is FTD and How Is It Connected to ALS.

What is “sporadic” ALS? Can it be genetic?

For the ninety to ninety-five percent of individuals living with ALS without an obvious family history, traditionally referred to as “sporadic”, it is estimated that between eleven to sixteen percent of cases are caused by known ALS variants.

This means individuals living with seemingly “sporadic” ALS might have acquired a spontaneous (acquired) variant throughout their lives, or most likely, their family history information was lacking, or the disease didn’t manifest in other family members.

There is current debate about how the terms “sporadic” and familial ALS are outdated and need to be reevaluated in terms of genetic ALS.

To date, many genes have been identified that when altered, can contribute to ALS. The four most common genetic causes of ALS are due to variants in four genes: C9ORF72, SOD1, FUS, and TARDBP. You can find more information on these genes below.

If I have a known ALS variant, will the variant be passed to my children?

A genetic counsellor is the best person to advise on the risk of an altered ALS gene being passed on to your children. In the majority of cases, the variant has a fifty percent chance of being passed on to a new generation, which is a dominant pattern of inheritance.

The parent has no control over whether the altered gene will be passed on to their children. Whether it is passed on or not is determined by genetic chance, and nothing can be done to change the pattern of inheritance.

If a child does not inherit the gene variant for ALS, they cannot pass it on to their own children.

What is gene penetrance?

The proportion of individuals with a genetic variant who will eventually develop the disease is known as penetrance. If a variant has eighty percent penetrance, eighty percent of gene carriers will eventually show symptoms of the disease.

Different variants have different penetrance, hence the importance of genetic counselling to assess your family risk.

Additional resources for an introduction to ALS genetics:

Introduction to ALS/MND Genetics (Video)

        A resource from the International Alliance of ALS/MND Associations on the basics of ALS genetics.

Alliance Introduction to Genetics: What is your genome?

Alliance Introduction to Genetics: What is genetic variation?

ALS/MND Genetics: Why is it important to understand genetic cause of disease?

       These three fact sheets by the International Alliance of ALS/MND Associations provide an overview of genetics.

ALS Canada Genetics Fact Sheet

       ALS Canada’s fact sheet provides an overview of genetics, including genetic testing.

ALS Canada Genetics Glossary

      ALS Canada has produced an easy-to-use resource to look up words you might come across related to genetics and ALS genetics.

ALS Canada Research Glossary

       ALS Canada has produced an easy-to-use resource to look up words you might come across related to genetics and ALS genetics.

More resources, including those relating to specific ALS genes, are located at the bottom of the page, under Additional ALS genetic resources.

1.2 ALS genes

Although many genes are associated with ALS, four are responsible for the most prevalent genetic variants related to ALS, based on current knowledge.

C9ORF72

Genetics:

  • A type of variant, called a repeat expansion, in a gene called C9ORF72, is attributed to causing ALS, as well as frontotemporal dementia (FTD).
  • A repeat expansion is when a section of the genetic code is repeated multiple times, impacting how the genetic code is read. The segment of the gene expanded in ALS/FTD is GGGGCC (each letter is a DNA base).
  • Research is ongoing to identify how variants in C9ORF72 contribute to ALS/FTD, as the role of the normal protein this gene encodes is still unclear. Multiple theories exist and are currently being studied worldwide, with researchers investigating whether it is the loss of the normal protein function that contributes to disease, if the altered RNA and/or protein gains a toxic function, or if it is a combination of both.
  • Since the discovery of C9ORF72’s connection to ALS and FTD in 2011, it has become one of the most studied topics in the field.

Prevalence and clinical presentation:

  • C9ORF72 variants are the most common genetic cause of ALS, believed to be responsible for approximately twenty-five to forty per cent of familial ALS cases and around five to ten per cent of individuals with no obvious family history*. The understanding of the likelihood that someone with a repeat expansion will develop disease, a term known as penetrance, is still evolving. A study published in 2023 suggests it might be lower than previously thought, but families can have unique experiences with the disease prevalence and onset. Results from this study should stimulate a much more focused examination and yield better answers about C9ORF72 penetrance in the future.
  • It is not clear yet what contributes to the development of ALS or FTD in an individual. Talking to a genetic counsellor is important for more information available on clinical presentation and family history where applicable.

*1, 2

Clinical trials and therapies:

  • There are currently no approved therapies targeting the C9ORF72 genetic variant that contributes to ALS/FTD.
  • A few clinical trials aimed at individuals with C9ORF72-ALS have been conducted in recent years, including:
  • It is expected that more clinical trials targeting C9ORF72-ALS/FTD will be available soon as a large proportion of work done in the field is focused on understanding and targeting mechanisms that lead to disease development.

You can also refer to End the Legacy’s C9ORF72 guide for more detailed information on C9ORF72.

SOD1

Genetics:

  • The SOD1 gene encodes the information to make a protein called superoxide dismutase 1. This protein helps cells to function properly by clearing toxic byproducts called reactive oxygen species. These byproducts are created naturally in the cell after normal cellular processes and must be broken down regularly to prevent cell damage.
  • Many variants in this gene can lead to a defective version of this protein, which becomes toxic and disrupts normal biology in cells, causing ALS.
  • Since 1993, when the SOD1 gene was discovered to be connected to ALS, over 200 different variants have been found in it.

Prevalence and clinical presentation:

  • Variants in the SOD1 gene are believed to cause ten to thirty percent of familial ALS cases and approximately one to four percent of individuals with no obvious family history*.
  • Different variants in this gene may be associated with a slower or faster progression of the disease. Talking to a genetic counsellor is important to gain more information on specific variants, the role of family history, and associated clinical presentation.
  • While the majority of individuals with SOD1 genetic variants are linked to known family history, several examples have been documented where variants are identified in individuals with no obvious hereditary link (these individuals will often be classified as having “sporadic ALS”) as mentioned above.

* 1, 2, 3

Clinical trials and therapies:

You can find current clinical trials targeting the SOD1 gene below.

 

TARDBP (TDP-43)

Genetics:

  • The TARDBP gene encodes the information to make an important protein called TAR DNA binding protein 43 (TDP-43). TDP-43 plays many roles in gene regulation, RNA and protein biology, and normal cell functioning. TDP-43 is typically found in the nucleus of the cell, which houses DNA, but in ALS, the protein ends up in the cytoplasm (the portion of the cell outside of the nucleus) and can form clumps called aggregates. Researchers are working to understand if the vulnerability of motor neurons to abnormal TDP-43 biology is due to a loss of its normal function in the nucleus, an extra toxic function in the nucleus or cytoplasm, or a combination of these.
  • The connection of ALS and frontotemporal dementia (FTD) to TARDBP genetic variants didn’t happen until 2006. Since then, over 50 different variants have also been found related to the TARDBP gene.
  • Since then, it has also been discovered that the majority of ALS cases have abnormal TDP-43 biology, regardless of a genetic variant. Currently, it is believed that ninety percent of ALS cases have abnormal TDP-43 biology, making restoration of its proper functioning an important target in ALS research.

Prevalence and clinical presentation:

  • Mutations in the TARDBP gene cause about four to five per cent of familial ALS cases and are found in about one per cent of individuals with no obvious family history.* TARDBP variants can also cause FTD or ALS/FTD. Talking to a genetic counsellor is important for more information available about clinical presentation.

*1

Clinical trials and therapies:

  • There are currently no clinical trials or therapies directly targeting the TARDBP genetic form of ALS.
  • However, given that TDP-43 biology is abnormal in most cases of ALS, most other trials not aimed specifically at SOD1 or FUS may be viable for someone with a TDP-43 variant. Additionally, certain clinical trials are targeting biology believed to be disrupted by abnormal TDP-43, such as those aiming to reduce levels of a protein called ataxin-2 (ATXN) or to restore stathmin-2 (STMN2). UNC13A, a target also believed to play a role in TDP-43 pathology, is being targeted by pharmaceutical companies such as AcuraStem and QurAlis, and clinical trials are expected soon.

 

FUS

Genetics:

  • The FUS gene contains the instructions to make a protein called fused in sarcoma (FUS). This protein is primarily located in the nucleus of the cell, and it is believed to contribute to normal cell function by playing a role in the complex biology between RNA and proteins. In ALS, researchers have discovered that variants in the FUS gene lead to creation of a defective FUS protein, causing toxicity to motor neurons.
  • Specific types of FUS variants have also been identified to contribute to juvenile onset ALS (occurring in individuals under 25 years old). Clinicians diagnosing an individual with younger onset of disease are encouraged to consider advising genetic counselling and testing, while informing them about the ongoing clinical trial by Ionis Pharmaceuticals, specifically targeting FUS.
  • Since the discovery of its connection to ALS and frontotemporal dementia (FTD) in 2009, 50 different variants have been found related to the FUS gene.

Prevalence and clinical presentation:

  • FUS genetic variants cause about three to six per cent of familial ALS cases and are found in about one per cent of individuals with no obvious family history*. FUS variants can also lead to frontotemporal dementia and ALS/FTD. In clinical presentation, FUS-ALS usually presents itself with an early-onset and faster rate of disease progression. Talking to a genetic counsellor is important for more information available about clinical presentation.

*1, 2, 3

Clinical trials and therapies:

  • There are currently no approved therapies targeting FUS-ALS.
  • You can find current clinical trials targeting the FUS gene below.
    • Ionis Pharmaceuticals is currently recruiting for a clinical trial of an antisense oligonucleotide (ASO) called ulefnersen, designed to target the reduction of FUS protein levels.

 

For information on other known ALS genes and for a comprehensive list, see below for our Advanced ALS Genetics Databases.

1.3 Genetic variation in different ethnic groups

ALS Canada recognizes that historically, scientific and genetic research has excluded or not accurately represented minorities and racialized groups. The majority of ALS research studies are from North America and Europe, primarily consisting of individuals of European descent. Other areas of the world might not have equivalent databases and available genetic information.

Some studies (1, 2) suggest different prevalence and variants between ethnic groups, but further research is needed. We also need to recognize that BIPOC groups often have a different healthcare experience, which creates further barriers to timely diagnosis and may impact the interpretation of these studies and databases. The country and geographic location of these studies are also important. We encourage you to consider the factors mentioned above and seek further research when possible.

We do know for certain that anyone, regardless of location and ethnicity, is at risk of being affected by a genetic form of ALS, although the exact genetic prevalence for different ethnic groups is not fully understood.

Please refer to our section below for studies focusing on BIPOC individuals affected by genetic ALS, and variation between ethnic groups.

1.4 Environmental factors for ALS

Different genes are associated with different likelihood of presenting symptoms, age of onset, and disease progression. For this reason, families with genetic forms of ALS may have individuals with vastly different experiences. Researchers are also studying environmental risk and protective factors of ALS, which can influence a person’s risk of developing the disease.

Proven risk factors for ALS are genetic variants and advanced age. ALS is also slightly more common in men than women.

For environmental risk factors, the only factor that is generally accepted to be associated with ALS is smoking. The exact mechanism and reasons why smoking could lead to a higher risk for ALS is unknown. However, given that smoking is a major risk factor for many, more common health problems, the risk of ALS is only one of the many reasons for recommending against it.

More research is needed and is currently being conducted to assess the influence of environmental factors on the disease onset and progression. There are current observational studies studying the link between ALS and other risk factors. However, it is difficult for these studies to prove with certainty that the risk factor caused or contributed to the disease, as it is not a controlled environment, and several different factors might be at play.

Due to this, we are unable to pinpoint any other specific causal factors for ALS. A workshop on guidance for pre-symptomatic genetic ALS and frontotemporal dementia (FTD), held in September 2023 concluded that, aside from not smoking for reasons beyond ALS and FTD, our current understanding of risk factors is not sufficient to warrant any recommendations for lifestyle changes to individuals at high genetic risk of these diseases. Once any summarized documentation from this workshop is available, a link will be provided here.

 

For additional research and resources:

Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

Smoking and risk of amyotrophic lateral sclerosis: a pooled analysis of five prospective cohorts

Environmental Factors ALS Association

Systematic and state-of the science review of the role of environmental factors in Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig’s Disease

For a summary: New meta-analysis explores potential environmental causes of ALS disease

Potential Environmental Factors in Amyotrophic Lateral Sclerosis

Risk factors for amyotrophic lateral sclerosis

ALS in the Military ALS Association

Military service and related risk factors for amyotrophic lateral sclerosis

 

It is essential to note that even if an individual attempts to avoid all the environmental factors mentioned above, this does not guarantee that they will not develop ALS. The exact triggers for the disease and how environmental factors interact with genetic variants remain unknown and will likely vary from individual to individual.

2. Information on genetic counselling and testing

2.1 Genetic counselling and testing

ALS Canada is committed to advancing and facilitating genetic testing practices across Canada, and we are advocating with clinicians nationally for broader coverage and access to counselling and testing. We are open to any individuals wanting to share their experiences with accessing genetic counselling and testing, either positive or negative. Information to better understand barriers to genetic counselling and testing can help to shape ALS Canada’s approach to advocacy moving forward. Please reach out to us at research@oldals.thedev.ca.

The decision to be tested is always yours. It is important to note that there are many variants in known ALS genes that don’t have sufficient research and information to fully understand their impact. Some physicians may hesitate to order genetic testing out of discomfort with not being able to provide comprehensive support to their patients trying to understand a complicated result.

However, given that ALS-associated genetic variants have been identified in cases with no identifiable family history of ALS (seemingly “sporadic” cases), and that therapies targeting these variants are entering or underway in clinical trials, many experts are supportive of offering genetic testing to everyone with a diagnosis of ALS, when accompanied by appropriate genetic counselling. The availability of genetic counselling and testing varies between provinces. Genetic testing practices in ALS are rapidly evolving, but they are not enough to meet everyone’s needs.

Genetic testing in an individual at risk of developing a disease (with a known family history), but who is not currently exhibiting any symptoms, is called predictive testing.

As a consensus, predictive genetic testing for ALS is not recommended for children under 18 years old, because they cannot give their full consent. It is also extremely rare for ALS to develop in childhood, although variants in the FUS gene are known to have an earlier onset of disease and this may result in rare exceptions for predictive testing in childhood. Rarely, other variants also show early onset. Talking to a genetic counsellor about your family risk is encouraged.

ALS Canada Webinar: Genetics and ALS

Our webinar provides introductory information on genetics and testing, including predictive testing.

Evidence-based consensus guidelines for ALS genetic testing and counseling

A consortium of experts in the United States have published the first peer-reviewed guidelines for genetic testing and counselling.

The importance of offering early genetic testing in everyone with amyotrophic lateral sclerosis

This is an opinion piece from global ALS leaders on how genetic testing practices should evolve.

International Alliance of ALS/MND Associations – Genetic Counselling & Testing Page

This is a great resource on genetic counselling & testing.

2.2 Genetic testing considerations

Decisions about genetic testing can always change, and an individual might reconsider their decision with further discussion and as ALS research progresses. Many individuals will choose to get tested before a major life decision (e.g., marriage or having children), or if they decide they want to participate in research and clinical trials.

When deciding about testing, exploring the reasons listed below with your family, genetic counsellor, and primary care physician can be helpful.

Reasons why someone might want genetic testing:

  • Reducing anxiety around the likelihood of developing ALS.
  • Having time to accept and process the results if they are positive.
  • Facilitating earlier diagnosis if symptoms manifest.
    • Earlier diagnosis of ALS can be significant in symptom management and eligibility for therapies and participation in clinical trials.
  • Empowering individuals to advocate for themselves and the community.
  • Finding a community, support, and services at an earlier stage.
  • Opportunity to participate in research and future therapeutic trials.
    • Participating in research can be an empowering way to face ALS. There are observational studies for individuals with a known variant of ALS but not showing symptoms, and these are extremely important in understanding ALS progression.
    • Additionally, interventional research with potential therapeutics for pre-symptomatic individuals is emerging.
  • Considering life decisions as well as understanding and mitigating potential risk factors.
    • This can be important as individuals consider career, health insurance, financial planning, and lifestyle choices.
  • Considering the decision to have children and family planning.

Reasons why someone might not want genetic testing:

  • Learning about the results of genetic testing for ALS can be an incredibly challenging moment.
    • Some individuals might not be at the right time in their lives to face the results, especially if they don’t have access to counsellors or professional help.
  • It can cause tension with other family members, who may not wish to know the test results.
  • Genetic status may inadvertently reveal the status of another family member (e.g., if someone wants to get tested but their parent does not, twins, etc.).
  • Individuals who have biological children might need to deal with feelings of anxiety related to ALS potentially being passed on.
  • Potentially experiencing guilt about testing negative if other family members test positive.
  • Positive results might mean having to rethink and change lifestyle, career, and insurance choices.

We encourage all families and individuals affected by a genetic form of ALS to stay on top of research breakthroughs and news relating to upcoming therapies in clinical trials as this is a rapidly advancing field.

For more information, you can refer to our fact sheet on genetic testing, which provides information on whether genetic testing is the right decision for you.

ALS Canada Genetic Testing Fact Sheet

2.3 Insurance and legal rights in Canada

ALS Canada is a member of the Canadian Coalition for Genetic Fairness (CCGF), and we actively lobbied the government to pass Bill S-201, which seeks to prohibit and prevent genetic discrimination. The bill received royal assent in May 2017 and was passed into law.

The law applies to everyone in Canada, including all employers and insurance providers (exceptions can be made for health care practitioners and researchers). In sum, the law:

  1. Prohibits mandatory genetic testing.
  2. Prohibits an individual or institution from requiring others to disclose the results of a genetic test.
  3. Prohibits the collection, use, or disclosure of genetic test results without the written consent.

However, it is important to note that family history may still be available for insurance providers when calculating rates and risk assessments. Please refer to the complete bill and to the resources below for more information.

Health care implications of the Genetic Non-Discrimination Act Protection for Canadians’ genetic information

I AM ALS – Canada’s Genetic Non-Discrimination Act: An Overview and Perspective

This webinar by I AM ALS provides more information on the Canadian Genetic Non-Discrimination Act, including its impact in research and clinical care.

2.4 Additional genetic testing-specific resources

Alliance genetic counselling and diagnostic genetic testing for ALS/MND and FTD webinar

Factsheet from the ALS Association: Familial Amyotrophic Lateral Sclerosis (FALS) and Genetic Testing

Les Turner ALS Foundation genetic testing for people living with ALS

United States specific: ALS Identified genetic testing

2.5 What is a variant of uncertain significance (VUS), and why are they important?

Sometimes, a genetic test result shows a change in the code (referred to as a variant) in a gene that we know is related to ALS, but the connection of that change to ALS is still unclear. This is called a variant of uncertain significance (VUS). For example, NEK1 is known as an ALS gene, but there are some changes in the NEK1 code that currently no one can reliably say causes or influences the development of the disease.

Sometimes the concern over how to explain a VUS to an individual, and the negative reaction and impact it can illicit, can be factors in a clinician’s hesitation to support genetic testing. This is also why pre- and post-test counselling is highly recommended. Often a VUS does not change clinical management, nor would predictive testing of family members be recommended. Sometimes there may be some follow up that the clinician can recommend trying to clarify the significance of the VUS, such as testing another family member with ALS (if applicable).

If someone has an identified VUS in a known ALS gene, it is important to note that the ALS research field has insufficient evidence to support it causing or increasing the risk of developing the disease. Research evidence is reviewed by top experts in the field on a regular basis. Research is also happening all the time to better understand ALS genetics and to inform the classification of genetic variants. A group of experts have even started a program where clinicians in the United States and Canada can get an assessment on any VUS identified in their patients.

There are resources that are frequently being updated with the latest evidence-based information on genetics, including when any VUS might have a status change to what is called a pathogenic or likely pathogenic variant, indicating that it is likely to cause or influence getting ALS. Some of these databases are on this page under additional resources. Asking a physician, genetic counsellor, or research@oldals.thedev.ca for assistance is always recommended.

Here is a geneticist describing VUS and how they are looked at by experts: VUS – The Most Maligned Result in Genetic Testing.

2.6 Accessing genetic testing in Canada

How can I get genetic testing in Canada?

Access to ALS genetic testing depends on whether you have a known family history, and/or if you are showing ALS symptoms.

  • With symptoms or a diagnosis
    • If you have an ALS diagnosis or have been referred to a CALS clinic (the Canadian ALS Research Network) and would like to access testing, please refer to your neurologist or ALS clinic for more information as this varies by clinic and province. Most CALS clinics will offer genetic testing for individuals with a known family history. Given that variants in certain ALS genes have been seen in people without an identifiable family history, many clinics will test anyone with an ALS diagnosis for changes in genes that could provide them opportunities for treatment or participation in a clinical trial. If you don’t have a family history but are interested in genetic testing, please speak to your neurologist or ALS specialist for options.
    • If you have a family history of ALS, and are experiencing symptoms that you are concerned may be related to ALS, ReferALS is a tool that can be provided to your doctor to help recognize early symptoms of ALS and encourage a referral to a neurologist or a specialized ALS clinic if needed.
  • Without symptoms or a diagnosis, but with a known family history
    • Genetic testing in an individual at risk of developing a disease, but who is not currently exhibiting any symptoms, is called predictive testing and often requires extensive genetic counselling. Currently, only some ALS clinics offer predictive testing to at-risk, asymptomatic family members of someone who has/had ALS with a confirmed genetic variant.
    • Please reach out to the ALS clinic who was responsible for providing care to your family member to discuss test options. You can also speak to your family physician about referrals to medical genetics and genetic counselling if you don’t have access to your family’s ALS clinic.
  • One of my family members had ALS, but we are not sure if they had an ALS variant. Can I access genetic testing for ALS?
    • The vast majority (about eighty to ninety percent) of ALS cases are not related to a known gene variant, meaning it is not passed on from parent to child. Therefore, if there is no known family history (i.e., multiple relatives carrying the genetic form of ALS) and it is an isolated case in the family, the likelihood of anyone else in the family getting ALS is similar to the general population. Some people may seek genetic testing for confirmation, but if you are not showing symptoms, access at present may be difficult without the confirmation of a family history.

ReferALS is a tool designed for community neurologists to recognize the symptoms of ALS, listing the common ALS symptoms and clinical features. You can read the symptoms and save the tool. If you or your family members start showing symptoms described in the tool, you can show your family doctor to encourage an expedited referral to a neurologist or even directly to a specialized ALS clinic.

2.7 Genetic counselling

Genetic counselling should always accompany genetic testing. Where possible, pre- and post-testing consultation is ideal. ALS genetics are complex, and our understanding is constantly evolving. Having appropriate genetic counselling before and after genetic testing can help someone make the best decision for themselves and their families and to better understand what the information might mean to them now or in the future.

Even if an individual doesn’t want to get tested at that moment, they can still meet with a genetic counsellor. The genetic counsellor can provide resources and genetic education, as well as discuss your family history and risk. They can also guide you through a potential testing plan, as well as testing alternatives such as DNA banking.

General Genetic Counselling FAQS

Alliance Genetic Counselling Webinar

ALS Association Genetic Counselling

3. Research opportunities

3.1 Mechanisms for therapies targeting genetic forms of ALS

To understand more about gene therapies, you can explore the resources below:

Alliance ALS/MND Genetics: What can we do about genetic ALS/MND?

The ALS Association Therapies Targeting ALS-Linked Genetic Mutations

The ALS Association Antisense Therapy for ALS

3.2 Clinical trials

There are ongoing studies to test experimental treatments that are aimed at individuals with specific ALS genetic variants. Please find an up-to-date list below.

For more information on clinical trials and for a list of all current ALS clinical trials in Canada, refer to our Clinical Trials page.

SOD1

Treatment

AMT-162

Company

uniQure

Type of treatment

Intrathecal AAV-microRNA

Phase of clinical trial

Phase 1

(not yet started)

Recruitment status

n/a

Canadian sites

n/a

Learn more

1

ALN-SOD

Regeneron

/Alnylam

RNA interference (RNAi)

Phase 1

(not yet started)

n/a

n/a

AP-101

AL-S Pharma

Intravenous antibody

Phase 2

Recruiting

Edmonton, London, Montreal (Neuro), Toronto

1

Tofersen

Biogen

Intrathecal antisense oligonucleotide

Phase 3

ATLAS

Recruiting

Calgary, Montreal (Neuro), Toronto

1, 2

FUS

Treatment

Ulefnersen

Company

Ionis

Type of treatment

Intrathecal ASO 

Phase of clinical trial

Phase 3

Recruitment status

Recruiting

Canadian sites

Montreal (Neuro)

Learn more

1

ATXN2

Treatment

BIIB-105

Company

Biogen

Type of treatment

Intrathecal ASO 

Phase of clinical trial

Phase 1/2

Recruitment status

Recruiting

Canadian sites

Montreal (Neuro)

Learn more

1

C9ORF72

There are currently no studies – more coming soon.

TARDBP

There are currently no studies – more coming soon.

3.3 Observational studies

Learning from individuals who carry specific genetic variants that increase their risk of ALS is critical for researchers’ ability to understand and develop treatments targeting those genes, but also for all people living with ALS. Contributing to research by enrolling in observational studies as a genetic carrier who is not experiencing ALS symptoms can help us understand the biological processes that might occur at the earliest stages of the disease. An ongoing, landmark clinical trial called ATLAS, is examining the ability of a treatment called tofersen to potentially slow down or stop the disease in people who carry SOD1 genetic variants before any symptoms arise, and it is a direct result of learning from SOD1 gene carriers in observational studies.

Please find some observational studies for ALS below:

ALS Families Project – Eleanor and Lou Gehrig ALS Center

ALS Signal – Explore ALS Clinical Research, Trials and Studies: Select Genetic ALS Observational Studies to see all current studies.

The DIALS (Dominant Inherited ALS) Network

PREVENT ALS

Pre-fALS (Pre-symptomatic Familial ALS)

4. ALS organizations, groups, and events focused on genetics

4.1 Organizations and groups

End The Legacy is a nonprofit organization dedicated to supporting and advocating for their community. Operating under the ALS Hope Foundation umbrella, these organizations together will develop educational programs about familial ALS and FTD, establish support groups for members of the familial ALS and FTD community, engage the medical community to establish guidelines for care of asymptomatic gene carriers, and advocate for the hundreds of thousands of people at higher risk for developing ALS or FTD through the inheritance of a genetic variant that runs in their family.

I AM ALS Familial ALS Team aims to raise awareness of familial ALS/FTD and engage, empower, and support the familial ALS community and advocate for them with ALS/FTD researchers and funders.

4.2 Webinars, conferences, and events

End the Legacy Genetic ALS / FTD Research Education Series:

Penn FTD Center Annual Familial Conference:

The 2024 conference has passed.

5. Additional ALS genetic resources

Below is a comprehensive list of existing ALS genetics resources mentioned throughout the ALS Canada Gene Hub.

5.1 Reading resources

5.2 Interactive resources

Les Turner My ALS decision tool for genetics

About this tool:

People living with ALS can get genetic testing to learn more about why they developed the condition. The information you learn from genetic testing can help you make decisions about your ALS care and plan for the future. If you have ALS, you can use this tool to learn about genetic testing and decide if it’s right for you.

5.3 Audio/video resources

5.4 Research studies focusing on variation between ethnic groups

For more non-genetic specific information:

Diversity and Inclusion Efforts at I AM ALS

Gaslighting: ALS, anti-Blackness, and medicine

5.5 ALS genetics resources for children and families

Meanwhile, for general resources on how to talk to children about ALS or FTD, please see below:

Family planning resources:

5.6 Additional Services support

ALS News Today ALS And Mental Health

6. Advanced learning resources

6.1 ALS genetic databases

The Amyotrophic Lateral Sclerosis online Database (ALSoD) is the longest serving and most comprehensive database of ALS genetics information.

The ClinGen ALS Gene Curation Expert panel is a global group of ALS genetic experts who evaluate evidence for genes’ abilities to confer symptoms of ALS. They monitor the latest discoveries and literature to determine whether a specific genetic variant is classified as one likely to lead to ALS or not, or when the evidence is insufficient, to state that a particular variant is one they are watching to learn more (Variant of Unknown Significance or VUS).

ClinGen ALS Gene Classification List

6.2 ALS genetics advanced reading

Research articles:

7. Other ALS Canada resources and support

8. ALS Canada funding and support

Over the years, ALS Canada has committed valuable research funding to better understand the genetics of ALS and finding novel gene therapies.

Project MinE

Project MinE is a pioneering and collaborative project that aims to understand the genetic basis of ALS and to ultimately find a cure for this devastating disease. It aims to analyze the whole genome sequence of at least 15,000 people living with ALS and 7,500 healthy controls. A whole genome sequence provides the entire set of someone’s DNA. Most ALS genetic studies to date have analyzed a portion of the DNA that only represents two per cent of their genome, making Project MinE a database of unprecedented power.

ALS Canada made a promise to contribute to the funding of 1,000 DNA samples. To date, we have provided approximately 750 samples.

ALS Canada’s Research Program will continue to support Project MinE in its work towards unraveling ALS.

ALS Canada Research Program funding

Impact Report Genetics & Gene Discovery Pages – coming soon!

9. Contact us

If you would like to provide any feedback on the ALS Canada Gene Hub, have additional questions about ALS genetics, or are part of an organization with additional resources for people affected by a genetic form of ALS, we encourage you to contact us at research@oldals.thedev.ca.

10. Sign up for future updates and initiatives

If there are significant research or clinical care updates on the ALS Canada Gene Hub, or if ALS Canada launches genetics-related initiatives and you wish to receive notifications, please provide your email below. 

Additionally, sign up for ALS Canada’s Newsletter for more information and news on ALS.