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Contribution to epileptic encephalopathy (EE) of mutations in  CACNA2D2 , encoding α2δ-2 subunit of Voltage Dependent Calcium Channels, is unclear. To date only one  CACNA2D2  mutation altering channel functionality has been identified in a single family. In the same family, a rare  CELSR3  polymorphism also segregated with disease. Involvement of  CACNA2D2  in EE is therefore not confirmed, while that of  CELSR3  is 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) in  CACNA2D2  and c.G6407A (p.Gly2136Asp) in  CELSR3 . Gene prioritization pointed to  CACNA2D2  as the most prominent candidate gene. The WES finding in  CACNA2D2  resulted to be statistically significant (p = 0.032), unlike that in  CELSR3 .  CACNA2D2  homozygous c.1295delA essentially abolished α2δ-2 expression. In summary, we identified a novel null  CACNA2D2  mutation associated to a clinical phenotype strikingly similar to the  Cacna2d2  null mouse model. Molecular and statistical analyses together argued in favor of a causal contribution of  CACNA2D2  mutations to EE, while suggested that finding in  CELSR3 , although potentially damaging, is likely incidental.

A Novel Null Homozygous Mutation Confirms CACNA2D2 as a Gene Mutated in Epileptic Encephalopathy