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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.

Authors :
Ohori S
Miyauchi A
Osaka H
Lourenco CM
Arakaki N
Sengoku T
Ogata K
Honjo RS
Kim CA
Mitsuhashi S
Frith MC
Seyama R
Tsuchida N
Uchiyama Y
Koshimizu E
Hamanaka K
Misawa K
Miyatake S
Mizuguchi T
Saito K
Fujita A
Matsumoto N
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.)

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