Dataset Information

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

ABSTRACT: Loss-, gain-of-function and mixed variants in SCN1A (Nav1.1 voltage-gated sodium channel) have been associated with a spectrum of neurologic disorders with different severity and drug-responsiveness. Most SCN1A 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 SCN1A 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 SCN1A 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.

SUBMITTER: Dinoi G

PROVIDER: S-EPMC11351414 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Dinoi Giorgia G Conte Elena E Palumbo Orazio O Benvenuto Mario M Coppola Maria Antonietta MA Palumbo Pietro P Lastella Patrizia P Boccanegra Brigida B Di Muro Ester E Castori Marco M Carella Massimo M Sciruicchio Vittorio V de Tommaso Marina M Liantonio Antonella A De Luca Annamaria A La Neve Angela A Imbrici Paola P

Biomedicines 20240731 8

Loss-, gain-of-function and mixed variants in SCN1A (Nav1.1 voltage-gated sodium channel) have been associated with a spectrum of neurologic disorders with different severity and drug-responsiveness. Most SCN1A 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 SCN1A variants, N935Y and H1393Q, occurs in two siblings prese ...[more]

PMID: 39200163

Similar Datasets

Project description:The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.

Dataset Information

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

Publications

The Biallelic Inheritance of Two Novel <i>SCN1A</i> Variants Results in Developmental and Epileptic Encephalopathy Responsive to Levetiracetam.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets