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. DGKD encodes 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 of DGKD by 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.

Sleep Related Epilepsy and Pharmacotherapy: An Insight

“…Based on the early onset of PS in these patients and the severity of their symptoms, the authors concluded that mutations in the SCN1A gene may regulate the severity of the syndrome rather than the genesis of the disorder (Martín Del Valle et al, 2011 ). In a very recent study, a 6-year old girl diagnosed with PS was presented with a de novo 2.6 Mb deletion in 22q11.2 and an additional 172 kb duplication in 2q37.1 (Bertini et al, 2017 ). Deletion in 22q11.2 was associated with loss of genes involved in brain function and development, such as RTN4R (reticulon four receptor, NOGO RECEPTOR) (Pan et al, 2005 ; Ramasamy et al, 2014 ), SNAP29 (synaptosomal-associated protein 29) and gene responsible for biogenesis of micro-mRNA, especially in mammalian brain such as DGCR8 (microprocessor complex subunit 8) (Cheng et al, 2014 ).…”

A familiar study on self-limited childhood epilepsy patients using hIPSC-derived neurons shows a bias towards immaturity at the morphological, electrophysiological and gene expression levels

“…Nevertheless, the genetic architecture for occipital SLCE is still not completely understood [ 2 ]. Oligogenic inheritance has been proposed for SLCEs, complicating the recognition of etiological genetic abnormalities in single-family studies [ 31 ]. It is important to emphasize that our studies were not designed to functionally prove a pathogenic role of the discovered FGD6 variant [ 32 ].…”