Whole exome sequencing identifies KCNH7 variants associated with epilepsy in children

Whole exome sequencing identifies KCNH7 variants associated with epilepsy in childrenThe KCNH7 (Potassium Voltage-Gated Channel Subfamily H Member 7) gene belongs to the Ether-A-Go-Go-Related Gene (ERG) subfamily of voltage-gated potassium channels.There are three members of the ERG family: ERG1, ERG2 and ERG3, with the latter being encoded by the KCNH7 gene.ERG1 is highly expressed in cardiomyocytes, and its mutations have been linked to arrhythmias, such as the long QT syndrome.1 Research on ERG2 is limited, while ERG3 is primarily expressed in neurons.The connection between the KCNH7 gene and neurological disorders remains to be elucidated.We performed trio whole exome sequencing in a cohort of 975 pediatric epilepsy patients.Among probands with negative results, potential candidate genes were screened (see supplemental methods), and the KCNH7 gene was one of them, displaying de novo variants in three unrelated probands in the cohort.The detailed clinical manifestations are summarized in Table S1.Case 1 presented with both generalized tonic-clonic seizure and focal motor seizure; case 2 was diagnosed with West syndrome; and case 3 exhibited focal motor seizure with brain structural abnormality detected by magnetic resonance imaging (MRI).Case 2 and 3 experienced development regression.All three cases were seizure-free for at least one year, with the use of one to three antiseizure medications.The three variants of the KCNH7 gene (NM_033272.4)were c.83A > G/p.K28R, c.1919A > G/p.E640G, and c.1324C > T/p.R442X.These variants had no recorded allele frequency in gnomAD.Statistical analysis revealed significant differences in aggregate frequencies of the mutant alleles between our cohort and controls in gnomAD (including all populations and East-Asian population) (3/1950 vs. 0/ 282730 in controls of gnomAD-all populations, P Z 3.209 Â 10 À7 ; 3/1950 vs. 0/19946 in controls of gnomAD-East-Asian population, P Z 0.001, respectively) (Table S2).The R442X in case 3 was a nonsense mutation, while the other two missense variants were predicted to be disease-Peer review under responsibility of Chongqing Medical University.