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NEFH
neurofilament heavy chain
NEFH encodes the neurofilament heavy chain protein, a structural component critical for maintaining the integrity and function of nerve cell axons. The NEFH gene provides instructions for making the heavy chain subunit of neurofilaments, which are rope-like structures that give nerve fibres their shape and strength.
NEFH is located on the long (q) arm of chromosome 22, at band 22q12.2. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 22 in the library →Overview
NEFH resides on chromosome 22 and encodes the neurofilament heavy chain, one of three subunits that form neurofilaments within nerve cells. Neurofilaments are intermediate filaments that provide structural support to axons, the long projections through which neurons transmit electrical signals. The heavy chain subunit plays a specialised role in stabilising neurofilament structure and regulating axon diameter, which influences how quickly nerve impulses travel.
Pathogenic changes in NEFH follow an autosomal dominant inheritance pattern, meaning a single altered copy of the gene can cause disease. These variants are recognised within the NHS Genomic Medicine Service as relevant to hereditary nerve disorders, appearing on multiple clinical gene panels used to diagnose unexplained neuropathy.
What the gene does
The neurofilament heavy chain protein functions as a key architectural element in the cytoskeleton of neurons. Neurofilaments assemble from three distinct chains - light, medium, and heavy - which intertwine to form stable filamentous networks throughout the axon. The heavy chain contributes side-arm projections that extend from the neurofilament core, creating spacing between adjacent filaments and determining the overall calibre of the axon.
Axon diameter directly affects conduction velocity, so proper neurofilament organisation is essential for efficient nerve signal transmission. The heavy chain's extended tail region contains multiple phosphorylation sites (primarily in the tail region) that regulate interactions between neurofilaments and other cytoskeletal elements, including microtubules and actin filaments. These interactions coordinate the transport of cellular cargo along axons and maintain the structural integrity needed for long-term neuronal survival. Disruption of neurofilament assembly or phosphorylation can lead to abnormal protein aggregation within nerve cells, impairing axonal transport and contributing to neurodegeneration.
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Chromosome location
NEFH is located on the long arm of chromosome 22 at position 12.2 (22q12.2). This chromosomal region contains several genes involved in neurological function. The genomic sequence of NEFH spans multiple exons that encode the 1,020 amino acid heavy chain protein.
Protein structure
The neurofilament heavy chain protein comprises three major structural regions. The N-terminal Head region (amino acids 1-100) contains a short disordered segment (amino acids 58-83) and anchors the protein during filament assembly. The central intermediate filament (IF) rod domain (based on structural studies, approximately amino acids 97-413) forms the backbone of neurofilament structure and consists of alternating coiled-coil segments - Coil 1A, Coil 1B, Coil 2A, and Coil 2B - separated by flexible linker regions (Linker 1, Linker 12, and Linker 2). These coiled-coil regions enable the protein to dimerise and ultimately assemble into higher-order filamentous structures.
The C-terminal Tail region (amino acids 414-1,020) is extensively disordered (amino acids 456-1,020) and contains approximately 30-50 KSP-like motifs spanning amino acids 525-826. This repetitive sequence provides multiple phosphorylation sites that regulate neurofilament spacing and interactions with other cellular structures.
Key variants
Pathogenic variants in NEFH are relatively uncommon but clinically significant causes of inherited neuropathy. Many reported disease-causing changes are missense variants that alter single amino acids within the rod domain, disrupting filament assembly. Some variants prevent normal protein folding, whilst others interfere with the ability of neurofilament subunits to interact correctly, leading to unstable or malformed filaments that aggregate within nerve cells.
Sample of pathogenic variants
9 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.3010_3011del | p.Asp1004fs | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease axonal type 2CC |
c.3057dup | p.Lys1020fs | Pathogenic/Likely pathogenic | ★★☆☆ | NEFH-related disorder |
c.3008_3009del | p.Lys1003fs | Pathogenic | ★☆☆☆ | not provided |
c.3017_3020dup | p.Pro1008fs | Pathogenic | - | Charcot-Marie-Tooth disease axonal type 2CC |
c.2752del | p.Glu918fs | Likely pathogenic | ★☆☆☆ | Charcot-Marie-Tooth disease axonal type 2CC |
c.3044_3045del | p.Lys1015fs | Likely pathogenic | ★☆☆☆ | Inborn genetic diseases |
c.3057_3060dup | p.Ter1021GluextTer? | Likely pathogenic | ★☆☆☆ | not provided |
c.883+1G>C | - | Likely pathogenic | ★☆☆☆ | Charcot-Marie-Tooth disease axonal type 2C |
c.646_653del | p.Leu216fs | Likely pathogenic | - | Charcot-Marie-Tooth disease axonal type 2CC |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in NEFH are associated with hereditary forms of peripheral neuropathy, conditions affecting the nerves outside the brain and spinal cord. Individuals with NEFH-related neuropathy typically experience progressive muscle weakness, reduced sensation in the hands and feet, and sometimes difficulties with balance and coordination. Symptoms often begin in adulthood, though onset age and severity can vary between families. The neuropathy results from the gradual degeneration of peripheral nerve axons, which lose their structural integrity when neurofilament networks are disrupted.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic NEFH variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
Within the NHS Genomic Medicine Service, NEFH appears on the Hereditary neuropathy panel and the Hereditary neuropathy or pain disorder panel (R78), both with green classification status. This classification indicates robust evidence linking NEFH variants to inherited nerve disorders, supporting its use in diagnostic genomic testing for patients with unexplained peripheral neuropathy or related symptoms.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the difference between the three neurofilament chains?
Neurofilaments contain light (NEFL), medium (NEFM), and heavy (NEFH) chain subunits that assemble together. The light and medium chains form the filament core, whilst the heavy chain extends side-arms that regulate spacing between filaments and control axon diameter.
How does NEFH inheritance work?
NEFH-related neuropathy follows an autosomal dominant pattern, meaning an affected individual has a 50% chance of passing the pathogenic variant to each child. A single altered gene copy is sufficient to cause disease.
Are NEFH variants a common cause of peripheral neuropathy?
NEFH variants account for a small proportion of hereditary neuropathy cases. Most inherited neuropathies result from variants in other genes, though NEFH is recognised as a clinically relevant cause within NHS diagnostic pathways.