FGF12 – Developmental and Epileptic Encephalopathy

Fibroblast growth factor 12 (FGF12) encodes an intracellular modulator of voltage-gated sodium channels NaV1.2, NaV1.5, and NaV1.6, delaying fast inactivation to promote neuronal excitability. Heterozygous de novo missense variants in FGF12 have been repeatedly identified in patients with developmental and epileptic encephalopathy (PMID:32645220).

In a cohort of 17 unrelated individuals, 14 carried the recurrent c.340G>A (p.Gly114Arg) variant and two carried c.148G>A (p.Gly50Ser), all arising de novo or via parental mosaicism, with seizure onset in the first month of life and severe to profound intellectual disability and behavioral disturbances in 82.3% and 64.7%, respectively (PMID:32645220).

Novel biallelic intragenic structural variants and a homozygous missense SNV were reported in two additional exome-negative DEE patients, confirming autosomal recessive loss-of-function as a second mechanism in DEE (PMID:37286232).

The variant spectrum now encompasses recurrent gain-of-function missense changes, autosomal dominant entire gene duplications, and rare biallelic loss-of-function SNVs/SVs, indicating both haploinsufficiency and dominant-negative or gain-of-function mechanisms.

Functional studies—including co-expression assays in neuronal-like cells, lymphoblastoid gene expression analyses, Drosophila in vivo modeling, and CRISPR-engineered mouse lines—demonstrate that FGF12 missense variants alter sodium channel gating and recapitulate epileptic phenotypes and SUDEP-like bradycardia (PMID:36029553; PMID:33982289).

Together, robust genetic and experimental data support a Strong association between FGF12 and developmental and epileptic encephalopathy, guiding diagnostic sequencing and potential sodium channel–targeted therapies.

References

• Epilepsia • 2020 • Defining the phenotype of FHF1 developmental and epileptic encephalopathy. PMID:32645220
• Life science alliance • 2023 • Biallelic structural variations within FGF12 detected by long-read sequencing in epilepsy. PMID:37286232
• EBioMedicine • 2022 • Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 being associated with developmental and epileptic encephalopathy and Autism spectrum disorder: A case series. PMID:36029553
• Epilepsia • 2021 • Early onset epilepsy and sudden unexpected death in epilepsy with cardiac arrhythmia in mice carrying the early infantile epileptic encephalopathy 47 gain-of-function FHF1(FGF12) missense mutation. PMID:33982289

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