Ohori, S., Miyauchi, A., Osaka, H., Lourenco, C.M., Arakaki, N., Sengoku, T., Ogata, K., Honjo, R.S., Kim, C.A., Mitsuhashi, S., Frith, M.C., Seyama, R., Tsuchida, N., Uchiyama, Y., Koshimizu, E., Hamanaka, K., Misawa, K., Miyatake, S., Mizuguchi, T., Saito, K., Fujita, A., Matsumoto, N. (2023). Biallelic structural variations within FGF12 detected by long-read sequencing in epilepsy.  Life Sci Alliance 6(8): e202302025.

FBrf0256751

Research paper

We discovered biallelic intragenic structural variations (SVs) in FGF12 by applying long-read whole genome sequencing to an exome-negative patient with developmental and epileptic encephalopathy (DEE). We also found another DEE patient carrying a biallelic (homozygous) single-nucleotide variant (SNV) in FGF12 that was detected by exome sequencing. FGF12 heterozygous recurrent missense variants with gain-of-function or heterozygous entire duplication of FGF12 are known causes of epilepsy, but biallelic SNVs/SVs have never been described. FGF12 encodes intracellular proteins interacting with the C-terminal domain of the alpha subunit of voltage-gated sodium channels 1.2, 1.5, and 1.6, promoting excitability by delaying fast inactivation of the channels. To validate the molecular pathomechanisms of these biallelic FGF12 SVs/SNV, highly sensitive gene expression analyses using lymphoblastoid cells from the patient with biallelic SVs, structural considerations, and Drosophila in vivo functional analysis of the SNV were performed, confirming loss-of-function. Our study highlights the importance of small SVs in Mendelian disorders, which may be overlooked by exome sequencing but can be detected efficiently by long-read whole genome sequencing, providing new insights into the pathomechanisms of human diseases.

PMC10248215 (PMC) (EuropePMC)