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Title: Biallelic structural variations within FGF12 detected by long-read sequencing in epilepsy
Authors: OHORI, SachikoMIYAUCHI, AkihikoOSAKA, HitoshiLOURENCO, Charles MarquesARAKAKI, NaohiroSENGOKU, ToruOGATA, KazuhiroHONJO, Rachel SayuriKIM, Chong AeMITSUHASHI, SatomiFRITH, Martin C.SEYAMA, RieTSUCHIDA, NaomiUCHIYAMA, YuriKOSHIMIZU, ErikoHAMANAKA, KoheiMISAWA, KazuharuMIYATAKE, SatokoSAITO, KuniakiMIZUGUCHI, TakeshiFUJITA, AtsushiMATSUMOTO, Naomichi
Citation: LIFE SCIENCE ALLIANCE, v.6, n.8, article ID 202302025, 16p, 2023
Abstract: 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 ex-citability 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 per-formed, confirming loss-of-function. Our study highlights the im-portance 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.
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Artigos e Materiais de Revistas Científicas - FM/MPE
Departamento de Pediatria - FM/MPE

Artigos e Materiais de Revistas Científicas - HC/ICr
Instituto da Criança - HC/ICr

Artigos e Materiais de Revistas Científicas - LIM/03
LIM/03 - Laboratório de Medicina Laboratorial

Artigos e Materiais de Revistas Científicas - LIM/36
LIM/36 - Laboratório de Pediatria Clínica

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