What are the recommendations for genetic testing for Amyotrophic Lateral Sclerosis (ALS)?

Genetic Testing for ALS

All persons with ALS should be offered genetic testing consisting of C9orf72 repeat expansion analysis plus sequencing of SOD1, FUS, and TARDBP as a minimum, regardless of family history. 1

Who Should Receive Genetic Testing

Definitive Recommendations

• Offer genetic testing to all ALS patients, including those without apparent family history, as approximately 10% of seemingly sporadic cases harbor pathogenic mutations 1
• Strongly recommend testing for patients with:
  • First-degree or second-degree relatives with ALS, frontotemporal dementia (FTD), or both 2
  • Early-onset disease (age <40 years) 1
  • Concurrent cognitive or behavioral symptoms suggesting FTD overlap 2

Testing Asymptomatic At-Risk Relatives

• Do not routinely offer predictive testing to asymptomatic at-risk family members unless they specifically request it or are enrolled in research programs 2
• When requested, provide comprehensive genetic counseling addressing the psychological, social, and ethical implications before proceeding 2, 3

Minimum Testing Panel

The core genetic testing panel must include: 1

• C9orf72 hexanucleotide repeat expansion (most common genetic cause, accounting for 40% of familial and 7% of sporadic ALS)
• SOD1 gene sequencing (second most common, 12-20% of familial cases)
• FUS gene sequencing
• TARDBP gene sequencing

This represents single-step testing that should be offered upfront rather than sequential gene-by-gene testing 1

Genetic Counseling Requirements

Pre-Test Counseling Must Address:

• Inheritance patterns and penetrance of identified mutations, noting that penetrance varies significantly by gene and even by specific mutation 2, 1
• Phenotypic pleiotropy, particularly the overlap between ALS and FTD, as some mutations (especially C9orf72) can cause either or both conditions 2
• Limitations of testing, including:
  • Variants of uncertain significance may be identified 1
  • Negative results do not exclude genetic etiology (only ~70% of familial ALS has identified genetic cause) 1
  • Multiple gene mutations can occur in the same individual 2
• Implications for family members, including potential need for cascade testing 3, 1
• Risk of genetic discrimination in employment and insurance, though protections exist in many jurisdictions 2

Post-Test Counseling Should Include:

• Client-centered discussion of results and their implications for prognosis, though genotype-phenotype correlations are often poor 3, 1
• Family communication strategies for disclosing results to at-risk relatives 3
• Information about research opportunities, including genotype-specific clinical trials and gene therapy studies 1, 4
• Reproductive counseling when appropriate 5

Laboratory Testing Standards

C9orf72 Testing Specifications:

• Must include both screening and sizing of the hexanucleotide repeat expansion 1
• Pathogenic threshold is typically ≥30 repeats, though intermediate expansions (20-29 repeats) require careful interpretation 1
• Southern blot or repeat-primed PCR should be used for accurate sizing 1

Sequencing Requirements:

• Next-generation sequencing with adequate coverage depth for SOD1, FUS, and TARDBP 1
• Copy number variant analysis should be included 1
• Testing should be performed in high-quality reference laboratories with appropriate quality control measures 6

Clinical Integration and Timing

When to Offer Testing:

• At or soon after diagnosis as part of multidisciplinary ALS care 3, 1
• Testing should not be delayed, as progressive disease may impair decision-making capacity 5
• Consider immediate referral to clinical genetics if available, though neurologists can facilitate testing directly with appropriate genetic counseling support 3, 1

Service Delivery Model:

• Multidisciplinary approach involving neurology, genetic counseling, and psychology services 2, 3
• Provide accessible, accurate information proactively to support informed decision-making 4
• Ensure continuity of care with follow-up after results disclosure 3

Special Considerations and Pitfalls

Common Challenges:

• Incomplete penetrance means that carrying a mutation does not guarantee disease development; this is particularly important for C9orf72 where penetrance is age-dependent and incomplete 2, 1
• Phenotypic variability within families carrying the same mutation can be substantial, making prognostication difficult 2
• Psychological impact of testing varies widely; both positive and negative results can cause significant distress including relief, guilt, worry, or in rare cases suicidal ideation 5
• Discordant results between clinical presentation and genetic findings can occur and require careful interpretation 5

Avoiding Pitfalls:

• Do not assume negative family history excludes genetic etiology—reduced penetrance, early deaths from other causes, and small family size can mask inheritance 1
• Do not order testing without adequate pre-test counseling about limitations and implications 3, 1
• Do not provide testing to asymptomatic relatives without comprehensive genetic counseling 2
• Ensure results are communicated in person when possible, not by mail or phone message alone 3

Insurance and Access

Insurance coverage of genetic testing and counseling services should be provided for all persons with ALS and their families to support clinical care and prevention efforts 6