FGF12 encodes a sodium channel-binding protein, member of the fibroblast growth factor homologous factor family, involved in the positive regulation of voltage-gated sodium channel activity. FGF12 was first reported in relation to developmental and epileptic encephalopathy in 2016 (Siekierska et al., PMIDs: 27164707). The mechanism of disease is heterozygous missense variants with a gain-of-function effect on sodium channel activity (PMID: 27164707, 36029553). The clinical presentation typically includes infantile-onset generalized and/or focal seizures, developmental delay, intellectual disability, and cerebellar or cerebral atrophy. Autism spectrum disorder has been reported in several cases. Three missense variants in this gene have been reported in at least 21 probands in 10 publications (PMIDs: 27164707, 27830185, 27872899, 28506426, 29699863, 30951195, 31292943, 32645220, 33287870, 36029553), including a recurrent variant, p.Arg52His, observed in 14 unrelated individuals. Variants usually occur de novo or are inherited from parents with germline or somatic mosaicism. In addition, two studies reported three probands with overlapping phenotypes carrying gene duplications resulting in loss of function (PMIDs: 28144627, 32524056, 36029553); these variants were not scored in this curation due to their different molecular mechanism. This gene-disease relationship is also supported by experimental evidence, including biochemical function (PMID: 33245860), functional alteration in cultured cells (PMIDs: 27164707, 36029553) and animal models in zebrafish (PMID: 27164707) and mice (PMID: 33982289). In summary, there is definitive evidence supporting the relationship between FGF12 and autosomal dominant developmental and epileptic encephalopathy. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 1, 2023 (SOP version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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