A Novel null homozygous mutation confirmsCACNA2D2as a gene mutated in epileptic encephalopathy

Contribution to epileptic encephalopathy (EE) of mutations inCACNA2D2, encoding α2δ-2 subunit of Voltage Dependent Calcium Channels, is unclear. To date only oneCACNA2D2mutation altering channel functionality has been identified in a single family. In the same family, a rareCELSR3polymorphism also segregated with disease. Involvement ofCACNA2D2in EE is therefore not confirmed, while that ofCELSR3is questionable. In a patient with epilepsy, dyskinesia, cerebellar atrophy, psychomotor delay and dysmorphic features, offspring to consanguineous parents, we performed whole exome sequencing (WES) for homozygosity mapping and mutation detection. WES identified extended autozygosity on chromosome 3, containing two novel homozygous candidate mutations: c.1295delA (p.Asn432fs) inCACNA2D2and c.G6407A (p.Gly2136Asp) inCELSR3. Gene prioritization pointed toCACNA2D2as the most prominent candidate gene. The WES finding inCACNA2D2resulted to be statistically significant (p = 0.032), unlike that inCELSR3.CACNA2D2homozygous c.1295delA essentially abolished α2δ-2 expression. In summary, we identified a novel nullCACNA2D2mutation associated to a clinical phenotype strikingly similar to theCacna2d2null mouse model. Molecular and statistical analyses together argued in favor of a causal contribution ofCACNA2D2mutations to EE, while suggested that finding inCELSR3, although potentially damaging, is likely incidental.