Inheritance Patterns

Inheritance Patterns of Amyotrophic Lateral Sclerosis (ALS): Familial vs. Sporadic 18

ALS can be categorized into both familial, with a notable family-related inherited genetic component to the disease, or sporadic, which lacks this familial component. 

Sporadic ALS has no evidence of Mendelian Inheritance:

Sporadic ALS is considered idiopathic (of unknown cause) and lacks a direct inheritance pattern. However, genetic susceptibility factors contribute to risk.

Genetic susceptibility is based on acquired mutations (sporatic or inherited permutations):

Known Familial ALS Genes: Pathogenic variants in genes like SOD1, C9ORF72, TARDBP, FUS, ANG, OPTN, and SETX are implicated, though they act as low-penetrance susceptibility factors (i.e., they increase risk but do not always result in disease)17,18,19.

Non-Familial ALS Genes: Variants in TBK1, ATXN2, NEK1, TP73, and SMN1 duplications linked to susceptibility (low penetrance)17,18,19. 

Rare and novel genetic variation is highly at play:

ALS has a high polygenic risk factor, as rare or novel coding variants in ALS genes are found in 28% of sporadic cases, with 4% having variants in multiple genes, suggesting a polygenic contribution.

Inheritance of familial or sporadic mutations are random, but susceptibility increases with prevalence of certain gene variations, and several errors during transcription, likely involving a combination of low-penetrance genetic variants, environmental factors, and epigenetic modifications16.

European Populations: C9ORF72 repeat expansions are most common (5.1%), followed by SOD1 (1.2%)16.

Asian Populations: SOD1 variants dominate (1.5%), with lower C9ORF72 prevalence (0.3%)16.

Mendelian Genetics can be observable in some Familially Aquired ALS cases:

Autosomal Dominant: Most common pattern. Key genes include C9ORF72(hexanucleotide repeat expansions), SOD1, TARDBP (TDP-43), and FUS. Offspring of an affected parent have a 50% chance of inheriting the mutation.

Autosomal Recessive: Rare. Examples include ALS2 (not mentioned in notes but recognized in literature) and certain OPTN variants.

X-Linked: Extremely rare (e.g., UBQLN2)18.

Key takeaways

Genetic Heterogeneity: Over 50 genes are associated with familial ALS, leading to variability in age of onset, progression, and symptoms.

Penetrance: the probability that a change will result in disease. In ALS, mutations are often incomplete (e.g., C9ORF72 penetrance is ~50–80% by age 80), meaning not all mutation carriers develop ALS.

Key Genes:

• C9ORF72: Most common cause in European populations (AD).

• SOD1: Second most common globally, with AD inheritance.

• FUS and TARDBP: Typically AD, linked to aggressive phenotypes.

Key Contrasts

• Familial ALS: Driven by high-penetrance mutations in single genes with clear Mendelian inheritance (mostly AD).

• Sporadic ALS: Involves polygenic, low-penetrance risk variants, often interacting with environmental factors (e.g., smoking, heavy metal exposure).

Emerging Concepts for a hopeful future of ALS research20,21 

• Oligogenic Inheritance: Some cases may require variants in multiple genes to manifest disease.

• Gene-Environment Interactions: Epigenetic changes (e.g., DNA methylation) may modulate risk in sporadic ALS.

Genetic Tools and Testing