When one gene does not explain it: HSP and the oligogenic model

A plain-language summary of a published scientific study. It is educational and does not replace medical advice.

The study: Pedullà G et al., Journal of Neurogenetics, published online 18 May 2026[1]. A mini-review of the literature. Only the abstract is freely available.

What the researchers studied

Hereditary spastic paraplegia (HSP) has long been considered monogenic: a variant in a single gene explains the condition. SPG4 (the SPAST gene), SPG7 and SPG11 remain the central examples[1]. Large genetic studies show, however, that up to 40% of cases have no single-gene explanation[1]. The authors reviewed the evidence for an oligogenic model, in which a few variants in different genes would add up and cause the condition together.

What they found

• Some statistical analyses and case reports, for example very rare variants in SYNE1, CAPN1 and PGAP1, suggest this mechanism might operate in some unsolved cases[1].
• The authors stress, however, that the evidence is preliminary and exploratory, not enough to treat the oligogenic model as validated[1].
• HSP genes seem to affect the same few processes in the cell: microtubules, the shape of the endoplasmic reticulum, fat metabolism, mitochondria and transport inside the cell[1].

What it means for families

• For SPG4, the classic explanation, a variant in SPAST, still holds[1].
• For families whose tests found no cause, the authors recommend exome or genome sequencing and careful genetic counselling. The oligogenic model should be used only as a hypothesis to test in selected cases, not as the default explanation[1].
• If several variants contribute, the chance of passing the condition on is expressed as a probability rather than a simple rule[1].

What the study does not tell us yet

This is a short review based on evidence that is still incomplete. The authors call for functional studies in cells and animals to understand how genes interact[1].