Novel Mutations in KCNJ10 Gene Associated With SeSAME Syndrome: Rare Disorder With Possible Common Mutation

Mutations in the KCNJ10 gene cause SeSAME syndrome, an autosomal recessive disorder characterised by seizures, sensorineural deafness, ataxia, intellectual impairment and electrolyte imbalances. KCNJ10 encodes an inwardly rectifying potassium channel Kir4.1, which is essential for preserving potassium ion homeostasis.

We assessed three Iranian families with SeSAME syndrome-like symptoms through whole-exome sequencing (WES). Segregation analysis and Sanger sequencing were also used to confirm identified mutations. Additionally, bioinformatic tools were utilised to predict the pathogenicity of the variants.

We identified two novel KCNJ10 mutations, c.967 T>C (p.Y323H) and c.352G>A (p.A118T) in three families. While there was no evidence of renal involvement, the probands from these families displayed early-onset seizures, ataxia, developmental delays and hearing abnormalities. Based on the Kir4.1 protein's structural modelling, the stability of the channel is influenced by both mutations. Precisely, p.A118T alters the transmembrane domain that is critical to channel operation, whereas p.Y323H modifies the cytoplasmic C-terminal domain, which may compromise intracellular localisation and regulation.

Our findings can expand the spectrum of mutations in the KCNJ10 gene and provide insight into the genotype-phenotype correlation in the SeSAME syndrome.