Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Na_v) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Na_v channels. Functional characterization of mutant FHF2A co-expressed with wild-type Na_v1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Na_v channel function.

成纤维细胞生长因子同源因子 (FHF) 是细胞内蛋白质，可调节大脑和其他组织中的电压门控钠 (Na _v ) 通道。FHF 功能障碍与包括癫痫在内的神经系统疾病有关。在这里，我们描述了两个兄弟姐妹对和三个无关的男性，他们在婴儿期出现顽固性局灶性癫痫发作和严重的发育迟缓。全外显子组测序在 FHF2 的 A 同种型 (FHF2A) 的 N 末端结构域中鉴定出半合子和杂合子变体。X连锁的FHF2基因（也称为FGF13) 具有替代的第一外显子，这些外显子产生多种 N 端序列不同的蛋白质同种型。变体位于 FHF2A 失活颗粒中的高度保守残基，与 Na _v通道固有的快速失活机制竞争。与野生型 Na _v 1.6 (SCN8A) 共表达的突变 FHF2A 的功能表征表明，突变 FHF2A 蛋白失去了诱导快速启动、长期阻断通道的能力，同时保留了促兴奋特性。这些功能获得效应可能会增加与FHF2变体的癫痫潜能一致的神经元兴奋性。我们的研究结果表明FHF2变异是婴儿发病的发育性和癫痫性脑病的原因，并强调了 FHF2A 同种型在调节 Na _v通道功能中的关键作用。