Mutation in the KCNA2 Gene, Heterozygous Variant of Uncertain Clinical Significance, First Case Description in the Scientific Medical Literature

Abstract

Introduction: Pathogenic variants in the KCNA2 gene (OMIM *176262) are associated with developmental and epileptic encephalopathy 32 (MIM #616366) with autosomal dominant inheritance.

Objectives: To present the first case in the scientific medical literature concerning a heterozygous variant of uncertain clinical significance (VUS) in the KCNA2 gene.

Methods: This involves a 17-year-old female patient with diffuse sensory motor axonal polyneuropathy and drug-resistant epilepsy, referred for evaluation, leading to a genetic assessment.

Results: A heterozygous variant of uncertain clinical significance (VUS) in the KCNA2 gene has been identified, involving the change of an adenine to a guanine at position 925 of the cDNA, in exon 3 of the gene (c.925A>G), resulting in a missense change from arginine to glycine at amino acid 309 (p.Arg309Gly) in the protein, an evolutionarily conserved amino acid. This variant is reported in the ClinVar database (Variant ID: 1313559) and classified as VUS. It is not listed in databases such as the Human Gene Mutation Data Base (HGMD), Leiden Open Variation Data Base (LOVD), or in the consulted scientific literature. The allelic frequency is unknown in the control population (gnomAD). In silico predictors (SFIT, Polyhen-2, LRT, MutationTaster, MutationAssesor, FATHHM, MetaSMV) classify this variant as deleterious.

Conclusions: This case is anecdotal and demonstrates our limited knowledge about the genetic correlation and neurological disorders. We hope that genetic research in this field will continue to develop.