Two Novel Variants in the CHRNA2 and SCN2A Genes in Italian Patients with Febrile Seizures

Abstract

Background: Febrile seizures (FSs) are the most common form of epilepsy in children aged between six months and five years. The exact cause is unknown, but several studies have demonstrated the importance of genetic predisposition, with increasing involvement of receptors and ion channels. The present study aims to identify novel pathogenic variants in Italian patients with FSs.

Methods: We performed targeted panel sequencing in a cohort of 21 patients with FSs. In silico analysis was performed to predict the pathogenic role of the resulting variants.

Results: We found two novel variants segregating in two families with FSs: c.1021C>G (p.Leu341Val) in the CHRNA2 gene and c.140A>G (p.Glu47Gly) in SCN2A.

Conclusions: The c.1021C>G (p.Leu341Val) variant leads to a codon change of highly conserved leucine to valine at position 341 and is located in segments M3 of the subunit, which is important for channel gating. The c.140A>G (p.Glu47Gly) variant causes a substitution of glutamic acid with glycine at position 47 of the protein, which is highly conserved across the species. Moreover, it is located in the N-terminal domain, a region commonly affected in ASD, which impacts the inactivation kinetics and voltage dependence of steady-state activation. Further analyses are needed to better explain the role of CHRNA2 and SCN2A in the development of febrile seizures.

Keywords: CHRNA2; SCN2A; febrile seizures; nicotinic acetylcholine receptor (nAChR); voltage-gated sodium channel (Nav) 1.2.

Figure 1

Pedigree of the families recruited, CHRNA2 and SCN2A sequence variants and conservation. (A1) Pedigree of Family 1. (A2) Pedigree of Family 2. The fully filled symbols represent the affected individuals; unfilled symbols, unaffected; arrow, proband; plus, individuals with variants. (B1) Electropherogram shows the wildtype sequence (at the top), the c.1021C>G variant in CHRNA2 in proband (II-1), her unaffected brother (II-2) and affected father (I-1) (middle), and the wildtype sequence in her unaffected mother (I-2) (at the bottom). (B2) The wildtype sequence (at the top), the c.140A>G variant in SCN2A in heterozygous proband (II-1) and his affected father (I-1) (middle), and the wildtype sequence in his unaffected mother I-2 (at the bottom). (C1) Alignment of CHRNA2 proteins shows high evolutionary conservation of Leucine 341. (C2) Alignment of SCN2A proteins shows high evolutionary conservation of glutamic acid 47.

Figure 2

Three-dimensional model of CHRNA2 protein. (A) Superposition between the wildtype and mutant protein model. (B) p.Leu341Val variant overlay, with leucine colored light brown and valine colored light blue.