CELSR3 variants are associated with febrile seizures and epilepsy with antecedent febrile seizures

Abstract

Aims To identify novel pathogenic gene of febrile seizures (FS)/epilepsy with antecedent FS (EFS+). Methods The trio‐based whole‐exome sequencing was performed in a cohort of 462 cases with FS/EFS+. Silico programs, sequence alignment, and protein modeling were used to predict the damaging of variants. Statistical testing was performed to analyze gene‐based burden of variants. Results Five heterozygous missense variants in CELSR3 were detected in five cases (families) with eight individuals (five females, three males) affected. Two variants were de novo, and three were identified in families with more than one individual affected. All the variants were predicted to be damaging in silico tools. Protein modeling showed that the variants resulted in disappearance of multiple hydrogen bonds and one disulfide bond, which potentially caused functional impairments of protein. The frequency of CELSR3 variants identified in this study was significantly higher than that in controls. All affected individuals were diagnosed with FS/EFS+, including six patients with FS and two patients with EFS+. All cases presented favorable outcomes without neurodevelopmental disorders. Conclusions CELSR3 variants are potentially associated with FS/EFS+.

Identification of novel pathogenic genes of childhood epileptic encephalopathies

“…CELSR2 (MIM*604265) encodes cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2), a transmembrane protein of the flamingo subfamily. Our previous studies have shown that two CELSR subfamily genes, CELSR1 and CELSR3, are associated with epilepsy 43,44 . CELSR2 is highly expressed in the brain with predominance in early life and plays a vital role in cell/cell signaling during nervous system formation 35 .…”

“…Regarding previously reported phenotypes, CELSR2 and TENM1 have not been defined to be associated with human diseases (https://omim.org). Our previous studies have shown that two genes of the CELSR subfamily, CELSR1 and CELSR3, are associated with epilepsy 25,26 . SBF1 encodes a member of the protein-tyrosine phosphatase family, which plays a vital role in cell growth and differentiation 27 .…”

Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies

“…While these domains are structurally well characterized and allow quite precise calculation, intracellular variants are limited in structural interpretation due to sparse common information on the threedimensional structure of the CTF. As indicated in the introduction, (rare) monoallelic variants in CELSR3 have been described to be involved in neural tube defects (NTDs) 4,12 , febrile seizures 13 and Tourette disorder 14 . However, the respective studies do not provide functional evidence to support this associations beyond doubt.…”

“…to failure in axon guidance or outgrowth [9][10][11] . Rare monoallelic variants in human CELSR3 have been associated with neural tube defects (NTDs) 4,12 , febrile seizures 13 and Tourette disorder 14 .…”

Efficient strategies based on behavioral and electrophysiological methods for epilepsy-related gene screening in the Drosophila model

“…Trio-based WES has been successful in defining the most likely epilepsy-implicated loci and screening out candidate genes, such as UNC13B, CELSR3 , and CDK19 in numerous studies ( Chung et al, 2020 ; Wang et al, 2021 ; Li et al, 2022 ). Besides, NGS analysis of a large cohort of patients with epilepsy revealed that approximately 14% of sequence changes in 70 common and rare mutations were detected as nonsense or deletion ( Lindy et al, 2018 ), while missense or frameshift mutations can also lead to loss-of-function (LOF) consequences ( Chen et al, 2017 ; Lindy et al, 2018 ).…”