Expanding the genotypic and phenotypic spectrum of EAST/SeSAME syndrome: identification of a novel homozygous mutation (c.194 G > A) in KCNJ10 gene.

introductionEAST/SeSAME syndrome is an ultra-rare disease characterized by seizures, epilepsy, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance and arises due to deleterious variants disrupting the function of the KCNJ10 gene. In this study, we investigated the clinical symptoms and genetic cause of the disease in a 10-year-old Iranian girl who presented with neurological, hearing, and renal problems.

methodsMagnetic resonance imaging (MRI), electroencephalography (EEG), and laboratory tests were performed to evaluate the clinical characteristics of the proband. Distinctively, disease-causing variants were identified using whole-exome sequencing (WES). Subsequently, in-silico analysis was conducted to forecast the pathogenic potential of the identified variant. ClusPro 2.0 and GROMACS software were used for computational docking and molecular dynamic simulation (MDS), respectively. EEG findings revealed epileptic signs.

resultsBrain MRI scan revealed no abnormalities. Through the application of WES, we detected a homozygous missense variant (NM_002241.5, c.194G > A, p.R65H) in the KCNJ10 gene. Direct sequencing detected this variant in a heterozygous state in the proband's parents. Additionally, this variant was detected in the aborted fetus of the family in a homozygous state. Computational analysis predicted that this variant would cause disease. Protein-protein docking analysis revealed that the p.R65H mutation significantly affects the binding pattern between KCNJ10 and KCNJ16 proteins. MDS demonstrated that the p.R65H variant notably altered the KCNJ10 protein structure, flexibility, stability, and degree of compaction.

conclusionThe detection of this variant broadens the range of KCNJ10 gene mutations linked to EAST/SeSAME syndrome, emphasizing the critical role of genetic testing in diagnosing this condition.