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

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.