RYR3 Variants Are Potentially Associated With Idiopathic (Non‐Lesional) Partial Epilepsy/Susceptibility of Seizures, Toward Understanding the Gene‐Disease Association by Genetic Dependent Nature

ABSTRACT The RYR3 gene encodes a brain‐type ryanodine receptor that functions to release calcium from intracellular storage and plays an essential role in calcium signaling. The associations between RYR3 variants and brain disorders remain unknown. We performed whole‐exome sequencing in patients with idiopathic (non‐lesional) partial epilepsy of unknown etiology. One de novo missense and six biallelic missense RYR3 variants were identified in seven unrelated cases. These variants had no or extremely low allele frequencies in the general population and were predicted to alter hydrogen bonds/decrease protein stability. Patients presented with partial seizures or secondarily generalized tonic–clonic seizures. All patients were seizure‐free with/without anti‐seizure treatment. Four showed antecedent febrile seizures, a typical susceptibility disorder that is related to the precipitating factor of fever. The genetic dependence nature (GDN) of RYR3 , which is defined as the distinct impact of the absence of a gene on normal life, is “obligatory” (causing disease phenotypes). Complete abolishing of RYR3 results in abnormal phenotypes instead of lethality, whereas partial/mild impairment (usually more common) is associated with mild disease or increased susceptibility to disease, consistent with our findings. RYR3 is therefore potentially a candidate disease gene or susceptibility gene for idiopathic partial epilepsy.