The Biallelic Inheritance of Two Novel SCN1A Variants Results in Developmental and Epileptic Encephalopathy Responsive to Levetiracetam

• Published in: Biomedicines 2024-07, Vol.12 (8), p.1698
• Main Authors: Dinoi, Giorgia, Conte, Elena, Palumbo, Orazio, Benvenuto, Mario, Coppola, Maria Antonietta, Palumbo, Pietro, Lastella, Patrizia, Boccanegra, Brigida, Di Muro, Ester, Castori, Marco, Carella, Massimo, Sciruicchio, Vittorio, de Tommaso, Marina, Liantonio, Antonella, De Luca, Annamaria, La Neve, Angela, Imbrici, Paola
• Format: Article
• Language: English
• Subjects: Amino acids; Analysis; Asymptomatic; biallelic inheritance; Care and treatment; Channel gating; Contraindications; Convulsions & seizures; Diagnosis; Encephalopathy; Epilepsy; Etiracetam; Families & family life; Genes; Genomes; Genotypes; Heredity; Mutagenesis; Mutation; Nav1.1; Parents & parenting; patch-clamp; Phenotypes; SCN1A; Siblings; Sodium; Sodium channels (voltage-gated)
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines12081698

Loss-, gain-of-function and mixed variants in (Nav1.1 voltage-gated sodium channel) have been associated with a spectrum of neurologic disorders with different severity and drug-responsiveness. Most variants are heterozygous changes occurring de novo or dominantly inherited; recessive inheritance has been reported in a few cases. Here, we report a family in which the biallelic inheritance of two novel variants, N935Y and H1393Q, occurs in two siblings presenting with drug-responsive developmental and epileptic encephalopathy and born to heterozygous asymptomatic parents. To assess the genotype-phenotype correlation and support the treatment choice, HEK 293 cells were transfected with different combinations of the WT and mutant cDNAs, and the resulting sodium currents were recorded through whole-cell patch-clamp. Functional studies showed that the N935Y and H1393Q channels and their combinations with the WT (WT + N935Y and WT + H1393Q) had current densities and biophysical properties comparable with those of their respective control conditions. This explains the asymptomatic condition of the probands' parents. The co-expression of the N935Y + H1393Q channels, mimicking the recessive inheritance of the two variants in siblings, showed ~20% reduced current amplitude compared with WT and with parental channels. This mild loss of Nav1.1 function may contribute in part to the disease pathogenesis, although other mechanisms may be involved.