title: A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy.
abstract: 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.
authors.affiliation: U.O. Genetica Medica, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pippucci
authors.affiliation: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy ; Dipartimento di Scienze Mediche Chirurgiche, University of Bologna, Bologna, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Parmeggiani
authors.affiliation: U.O. Genetica Medica, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Palombo
authors.affiliation: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy ; Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Maresca
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy ; Center for Advanced Studies, Research, and Development in Sardinia (CRS4), AGCT Program, Parco Scientifico e tecnologico della Sardegna, Pula, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Angius
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Crisponi
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy ; Dipartimento di Scienze Biomediche, University of Sassari, Sassari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucca
authors.affiliation: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy ; Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.affiliation: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy ; Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, Italy.
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Valentino
authors.affiliation: U.O. Genetica Medica, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy ; Dipartimento di Scienze Mediche Chirurgiche, University of Bologna, Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.affiliation: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy ; Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
mesh_terms: D015220:Calcium Channels / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D013036:Spasms, Infantile / Q000235:genetics*
chemical_list: C480968:CACNA2D2 protein, human; D015220:Calcium Channels