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Biallelic structural variations within FGF12 detected by long-read sequencing in epilepsy.
Biallelic structural variations within FGF12 detected by long-read sequencing in epilepsy.
- Source :
-
Life science alliance [Life Sci Alliance] 2023 Jun 07; Vol. 6 (8). Date of Electronic Publication: 2023 Jun 07 (Print Publication: 2023). - Publication Year :
- 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 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.<br /> (© 2023 Ohori et al.)
- Subjects :
- Humans
Fibroblast Growth Factors
Mutation, Missense
Epilepsy genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2575-1077
- Volume :
- 6
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Life science alliance
- Publication Type :
- Academic Journal
- Accession number :
- 37286232
- Full Text :
- https://doi.org/10.26508/lsa.202302025