Eight novel genes expand the clinical and molecular spectrum of peripheral neuropathy

Peripheral neuropathies are disorders of the nerves outside the brain and spinal cord, often causing numbness, pain, weakness, and balance problems that start in the hands and feet.

“Despite major advances, the underlying cause remains unknown for many patients, even after standard clinical work-ups and genetic testing,” says Ayşe Candayan, postdoctoral researcher in the Jordanova lab at the VIB-UAntwerp Center for Molecular Neurology.

But 2025 marked a significant year for peripheral neuropathy genetics. New disease genes and mechanisms refined diagnostic pathways and opened new directions for functional and translational research. Just as importantly, these discoveries broadened how clinicians and geneticists think about 'where to look' for causes of neuropathy, especially in cases that do not fit classical patterns.

Familiar genes

A recurring theme in recent neuropathy genetics is that genes previously associated with severe central nervous system disorders can also cause primarily peripheral disease, depending on the type and strength of the variant.

“We showed that specific genetic changes in POLR3A can cause early-onset peripheral neuropathy, distinct from the severe neurodevelopmental disorders previously linked to the gene,” says Candayan. “This work expands the clinical spectrum of POLR3A and clarifies how different variant types can lead to markedly different presentations.”

A similar principle emerged for DARS2: while DARS2 variants are classically associated with disorders affecting the brain and spinal cord, milder changes can instead manifest as axonal Charcot-Marie-Tooth disease, largely sparing the central nervous system while still affecting long peripheral nerves.

Familiar clinical presentations

Sometimes it is not the gene, but the way the patient presents, that looks familiar. Several newly identified genetic neuropathies resemble acquired, immune-mediated conditions, making diagnosis particularly challenging, and raising the risk of inappropriate treatment.

One example is RCC1, where variants were shown to cause a severe childhood neuropathy that may begin abruptly after infection and can resemble Guillain-Barré syndrome. Unlike this immune condition, however, the disease is genetic in origin and follows a different course, linked to disrupted intracellular transport processes.

Variants in PIGG were found to expand the spectrum of GPI-anchor deficiencies to include a childhood-onset motor neuropathy with nerve conduction blocks, a feature more commonly associated with chronic inflammatory demyelinating polyneuropathy or CIDP.

Finally, in another study involving the Jordanova lab, variants in ARHGAP19 were shown to cause a neuropathy with subacute progression and slowed nerve conduction. Because the presentation can mimic CIDP, patients may be misdiagnosed and exposed to ineffective immunotherapy.

A broader view of disease mechanisms

Collectively, last year’s findings expand the molecular view of peripheral neuropathy. Rather than being limited to defects in structural nerve proteins, the newly implicated mechanisms point to disruptions in fundamental cellular processes, such as mitochondrial biology (COX18), tRNA-related homeostasis (POLR3A), nucleocytoplasmic transport (RCC1), and autophagy (KCTD11).

A few of the new genetic discoveries were enabled by long-read sequencing, which overcomes some key limitations of standard short-read approaches. Traditional sequencing reads DNA in short fragments and can miss complex variation, leaving many patients without a molecular diagnosis. Long-read sequencing can capture much longer stretches of DNA, making it more effective for detecting structural changes and splicing-related mechanisms.

“This approach was essential in our work on COX18, where long-read methods revealed complex splicing defects that are effectively invisible to conventional sequencing,” says Candayan.

In parallel, collaborative platforms such as GeneMatcher, together with tools like AlphaFold for protein structure prediction, have accelerated how quickly researchers can connect cases, interpret variants, and converge on convincing evidence.

Ayşe Candayan ©VIB-Ine DehandschutterAyşe Candayan and Albena Jordanova in the lab ©VIB-Elisabeth Verwaest

Reaching for the high-hanging fruit

“Long-read sequencing helped us pick up the pace for gene discovery after a plateau around 2018-2019,” Candayan says, “but the bigger shift is that we’re increasingly past the low-hanging fruit.”

To make new discoveries, we have to look in unlikely corners, she says, and that requires a change in mindset.

“Unexpected links require scale and coordination. For example, we could only demonstrate that heterozygous variants in POLR3A can also cause peripheral neuropathy by building a broad consortium and working together across institutes,” Candayan says. “Data is shared more readily than in the past, and it matters: collaboration is what turns a single family into a robust gene–disease association.”

Liesbeth Aerts

Research communicator

• liesbeth@beakon.be