title: A Case of 22q11 Deletion Syndrome (22q11DS) with a Panayiotopoulos Epileptic Pattern: Are Additional Copy-Number Variations a Possible Second Hit in Modulating the 22q11DS Phenotype?
abstract: "22q11 deletion syndrome" (22q11DS) is a rare genetic syndrome, in which most patients share the same deletion, but their clinical features may vary a great deal. The genetic mechanisms underlying the variable expressivity and reduced penetrance of 22q11DS still have to be fully elucidated. Epilepsy has been reported in about 15.2% of the patients; however, few studies have focused on this topic, and in most cases, a detailed epileptic profile is missing. Since only a minority of patients experience epileptic seizures, 22q11deletion can be considered a predisposing factor, which is not sufficient "per se" to cause epilepsy; to date, no candidate gene for epilepsy has been identified in the deleted region. We report on a 6-year-old girl with 22q11DS presenting a form of epilepsy that can be classified as "Panayiotopoulos syndrome." Array CGH revealed an additional microduplication of 172 kb in 2q37, harboring three genes. One of these,DGKD(diacylglycerol kinase delta), is interrupted by the distal breakpoint of the duplication.DGKDencodes a cytoplasmic enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. This is an important second messenger in a pathway of lipid signaling that has been implicated in epilepsy and other neurological diseases. Disruption ofDGKDby a t(X;2) has been previously reported in a patient with epilepsy. The 2q37 microduplication was inherited from her mother, who never experienced epileptic seizures, thus this imbalance is not "per se" sufficient to cause epilepsy. It can be hypothesized that the epileptic phenotype is provoked by the simultaneous presence of 22q11.2 deletion and 2q37 duplication. It has been shown that rare additional copy-number variations (CNVs) outside the 22q11.2 region may modulate the risk of congenital heart defects. It is possible that also for the epileptic phenotype, the additional CNVs may represent an important modifying factor underlying the variable expressivity and incomplete penetrance in the 22q11DS.
authors.affiliation: Cytogenetics and Molecular Genetics Unit, Azienda Ospedaliero-Universitaria Pisana , Pisa , Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Bertini
authors.affiliation: Cytogenetics and Molecular Genetics Unit, Azienda Ospedaliero-Universitaria Pisana , Pisa , Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Valetto
authors.affiliation: Cytogenetics and Molecular Genetics Unit, Azienda Ospedaliero-Universitaria Pisana , Pisa , Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Azzarà
authors.affiliation: Laboratory of Immunology, University of Pisa , Pisa , Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Legitimo
authors.affiliation: Laboratory of Immunology, University of Pisa, Pisa, Italy; Section of Pediatric Neurology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saggese
authors.affiliation: Laboratory of Immunology, University of Pisa , Pisa , Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Consolini
authors.affiliation: Section of Pediatric Neurology, Azienda Ospedaliero-Universitaria Pisana , Pisa , Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Orsini
authors.affiliation: Section of Pediatric Neurology, Azienda Ospedaliero-Universitaria Pisana , Pisa , Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Bonuccelli
keywords: 22q11 deletion syndrome; 2q37; DGKD; array CGH; copy-number variations; epilepsy