In ALS, one of the histopathological features of disease is the presence of cytoplasmic inclusions containing intermediate filament proteins (light, medium, and heavy) in axonal spheroids and within the cell body of motor neurons 5, 6, 7, 8.

In neurons, assembly of the light, medium and heavy neurofilament proteins is required in a specific stoichiometry (4:2:1 respectively) to form the foundations of the neuronal cytoskeleton 1, 2, to facilitate axonal transport by maintaining axonal diameter, and to direct and position mitochondria along the axon 3, 4. Neurofilament heavy protein (NEFH) is a type IV intermediate filament. These results suggest that the 9 and 10 TTTA motif length may have a protective advantage for potentially lowering the risk of sALS and delaying the age of disease onset, however, these results need to be replicated in larger multicenter and multi-ethnic cohorts. Furthermore, carriage of the 10 TTTA allele was associated with a 2.7 year later age of disease onset in the larger combined sALS cohort ( p = 0.02). Stratification according to site of disease onset revealed that the 9 TTTA allele was associated with reduced disease risk, specifically confined to spinal-onset sALS patients in the Duke cohort ( p = 0.001). In the current study, a candidate tetranucleotide (TTTA) repeat variant in NEFH was selected using an in-silico short structural variant (SSV) evaluation algorithm and investigated in two cohorts of North American sALS patients, both separately and combined (Duke cohort n = 138, Coriell cohort n = 333 combined cohort n = 471), compared to a group of healthy controls from the Coriell Institute biobank (n = 496). Neurofilament heavy (NEFH) is one of the critical proteins required for the formation of the neuronal cytoskeleton and polymorphisms in NEFH are reported as a rare cause of sporadic ALS (sALS).

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