Whole exome sequencing revealed ultra-rare genetic variations in juvenile myoclonic epilepsy

Juvenile Myoclonic Epilepsy (JME) is the most common adolescent and adult-onset genetic generalized epilepsy. In this study, we aimed to identify all rare variants present in exons and exon-intron junctions in patients who met the criteria of JME, determine potentially pathogenic variants, and find the assumed genotype/phenotype correlation between the identified variants and the JME clinical features.

Whole Exome Sequencing (WES) was performed for ten JME patients from different families. Validation, co-segregation and mode of inheritance were determined using Sanger DNA sequencing.

Predictable damaging variants were found in six families with positive co-segregation. Eight variants in eight genes (SCN1B, KCNQ2, CACNA1I, GABRA3, BSN, RYR3, SEZ6, and RYR2) and one novel variant in (TNR) gene were found to be associated with JME. All these genes play key roles in the interactions between neurons, neurotransmitter release, and maintenance of the balance between neuronal excitation and inhibition.

Since the identified genes are involved in the molecular mechanisms underlying seizures, such variants can potentially be epileptogenic. In conclusion, the identified variants that co-segregate with JME symptoms and likely contribute in creating the adequate genetic background for the JME phenotype.