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FGF12
fibroblast growth factor 12
FGF12 encodes a member of the fibroblast growth factor family that regulates neuronal excitability and is associated with epilepsy and intellectual disability. The FGF12 gene encodes a protein from the fibroblast growth factor family that functions differently from classical growth factors.
FGF12 is located on the long (q) arm of chromosome 3, at band 3q28-q29. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 3 in the library →Overview
FGF12 encodes fibroblast growth factor 12, an intracellular protein that plays a critical role in neuronal function. Unlike most members of the fibroblast growth factor family, which are secreted signalling molecules, FGF12 remains within cells and acts as a regulator of neuronal excitability. The protein is highly expressed in the nervous system, where it interacts with voltage-gated sodium channels to modulate electrical activity.
Pathogenic variants in FGF12 have been linked to early-onset epilepsy and intellectual disability, reflecting the protein's importance in brain development and function. The gene follows an autosomal dominant inheritance pattern, meaning a single altered copy can cause disease. Understanding FGF12 function helps explain why disruptions to neuronal signalling can lead to seizures and cognitive impairment.
What the gene does
The FGF12 protein serves as an intracellular modulator of neuronal excitability rather than a classical growth factor. It functions primarily by interacting with voltage-gated sodium channels, which are essential for generating and propagating electrical signals in nerve cells. By binding to the intracellular domains of these channels, FGF12 influences their availability and responsiveness, thereby affecting how readily neurons fire action potentials.
This regulatory function is particularly important in the brain, where precise control of neuronal excitability maintains the balance between excitation and inhibition. The protein is able to move between the cytoplasm and nucleus, suggesting additional roles in gene regulation beyond its primary function at sodium channels. FGF12 is most abundant during nervous system development and in mature brain tissue, where it contributes to establishing and maintaining appropriate patterns of neuronal activity. Disruption of these regulatory mechanisms can destabilise neuronal networks, leading to seizures and developmental delays.
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Chromosome location
FGF12 is located on the long arm of chromosome 3, specifically at the cytogenetic band 3q28-q29. This chromosomal region contains multiple genes involved in various cellular processes. The precise genomic context of FGF12 places it among a cluster of genes active in neurological development and function.
Protein structure
The FGF12 protein comprises 243 amino acids and is organised into several functional regions. The protein contains a nuclear localisation signal that enables it to enter the cell nucleus, suggesting roles beyond its well-characterised function at neuronal sodium channels. The protein structure includes disordered regions-segments without a fixed three-dimensional shape-which often serve to mediate interactions with other proteins and provide flexibility in binding to multiple partners. This is consistent with FGF12's role as a regulatory adaptor protein. The central core contains the fibroblast growth factor homology domain, which is responsible for interacting with sodium channels and mediating the protein's regulatory functions.
Key variants
Pathogenic variants in FGF12 disrupt the protein's ability to regulate neuronal excitability effectively. Most disease-causing changes are missense variants that alter single amino acids in functionally critical regions, affecting how the protein interacts with voltage-gated sodium channels. These variants typically follow an autosomal dominant pattern, where one altered copy is sufficient to cause symptoms. The spectrum of variants identified reflects the gene's intolerance to functional disruption, with loss-of-function changes particularly likely to cause disease.
Sample of pathogenic variants
5 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.148G>A | p.Gly50Ser | Pathogenic/Likely pathogenic | ★★☆☆ | FGF12-related disorders |
c.155G>A | p.Arg52His | Pathogenic/Likely pathogenic | ★★☆☆ | Developmental and epileptic encephalopathy, 47 |
c.14-47517G>C | - | Likely pathogenic | ★☆☆☆ | not provided |
c.341G>A | p.Gly114Glu | Likely pathogenic | ★☆☆☆ | Developmental and epileptic encephalopathy, 47 |
c.454del | p.His152fs | Likely pathogenic | ★☆☆☆ | not provided |
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 FGF12 are primarily associated with neurological conditions characterised by seizures and developmental delay. Affected individuals typically present with early-onset epilepsy, often beginning in infancy or early childhood, alongside intellectual disability of varying severity. The epilepsy phenotype can include multiple seizure types and may be difficult to control with standard anti-epileptic medications. Some individuals also exhibit additional neurological features such as movement disorders or behavioural difficulties. The clinical presentation reflects the critical role of FGF12 in establishing and maintaining normal brain function during development and throughout life.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic FGF12 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
FGF12 is included on multiple NHS Genomic Medicine Service gene panels relevant to neurological conditions. The gene holds green classification status (indicating definitive evidence) on the DDG2P panel. It also appears with green status on both the Early Onset or Syndromic Epilepsy panel (rated R59) and the Intellectual Disability panel (rated R29). These inclusions reflect the gene's established clinical relevance for diagnosing individuals with unexplained seizures or cognitive impairment, particularly when symptoms begin early in life.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is FGF12 different from other fibroblast growth factors?
Unlike classical fibroblast growth factors that are secreted and act as signalling molecules between cells, FGF12 remains inside neurons and functions as an intracellular regulator of sodium channel activity. It does not bind to fibroblast growth factor receptors on the cell surface.
What inheritance pattern do FGF12 variants follow?
FGF12 variants typically follow an autosomal dominant pattern, meaning a single altered copy inherited from one parent is sufficient to cause disease. Each child of an affected parent has a 50% chance of inheriting the variant.
Why does FGF12 dysfunction cause seizures?
FGF12 helps regulate voltage-gated sodium channels that control electrical activity in neurons. When the protein is disrupted, these channels may become overactive or dysregulated, destabilising the balance of excitation and inhibition in brain circuits and making seizures more likely to occur.