Array comparative genomic hybridization: Results from an adult population with drug-resistant epilepsy and co-morbidities

Abstract

BackgroundThe emergence of array comparative genomic hybridization (array CGH) as a diagnostic tool in molecular genetics has facilitated recognition of microdeletions and microduplications as risk factors for both generalised and focal epilepsies. Furthermore, there is evidence that some microdeletions/duplications, such as the 15q13.3 deletion predispose to a range of neuropsychiatric disorders, including intellectual disability (ID), autism, schizophrenia and epilepsy.We hypothesised that array CGH would reveal relevant findings in an adult patient group with epilepsy and complex phenotypes.Methods82 patients (54 from the National Hospital for Neurology and Neurosurgery and 28 from King’s College Hospital) with drug-resistant epilepsy and co-morbidities had array CGH. Separate clinicians ordered array CGH and separate platforms were used at the two sites.ResultsIn the two independent groups we identified copy number variants judged to be of pathogenic significance in 13.5% (7/52) and 20% (5/25) respectively, noting that slightly different selection criteria were used, giving an overall yield of 15.6%. Sixty-nine variants of unknown significance were also identified in the group from the National Hospital for Neurology and Neurosurgery and 5 from the King’s College Hospital patient group.ConclusionWe conclude that array CGH be considered an important investigation in adults with complicated epilepsy and, at least at present for selected patients, should join the diagnostic repertoire of clinical history and examination, neuroimaging, electroencephalography and other indicated investigations in generating a more complete formulation of an individual’s epilepsy.

Chromosomal microaberrations in patients with epilepsy, intellectual disability, and congenital anomalies

“…Thus, incomplete penetrance and a high phenotypic variability were assumed. Galizia et al (18) found a gain involving CHRNA7 in a patient with epilepsy and brain malformations, and they suggested that either the duplication or the structural change could be the 'second hit'. Likewise, the maternally inherited duplication 15q25.1 in patient 9 which affects the genes CHRNA3 and CHRNB4 may have an effect in the etiology of epilepsy, possibly in association with a second hit or a modifier.…”

The human clinical phenotypes of altered CHRNA7 copy number

“…Transmitting parents, with and without phenotypes, were included. In total, 90 individuals with duplications involving CHRNA7 were available for review [1,16,17,27,31,32,42,43,46–49,53,57–59]. …”

“…The most common duplications of CHRNA7 , with an estimated prevalence of one in 174 to one in 186 individuals, encompass only the gene itself or include the first exon of OTUD7A , with 67 cases identified in the literature for which clinical data are available [1,3,31,32,46,47,53,57–59]. Of these, 53 (79.1%) have unknown inheritance (Figures 2 & 3).…”

Clinical review of genetic epileptic encephalopathies

“…If the physical examination does not reveal a recognizable syndrome, it is reasonable to proceed with array comparative genomic hybridization (CGH) to assess for copy number variations that may explain the phenotype [187]. Array CGH has been helpful in detecting chromosomal causes of epilepsy in 10–30% of patients with seizures [188–190]. …”