Article

Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders

Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.27). 10/2012; 159B(7):760-71. DOI: 10.1002/ajmg.b.32081
Source: PubMed

ABSTRACT Copy-number variants (CNVs) collectively represent an important cause of neurodevelopmental disorders such as developmental delay (DD)/intellectual disability (ID), autism, and epilepsy. In contrast to DD/ID, for which the application of microarray techniques enables detection of pathogenic CNVs in ∼10-20% of patients, there are only few studies of the role of CNVs in epilepsy and genetic etiology in the vast majority of cases remains unknown. We have applied whole-genome exon-targeted oligonucleotide array comparative genomic hybridization (array CGH) to a cohort of 102 patients with various types of epilepsy with or without additional neurodevelopmental abnormalities. Chromosomal microarray analysis revealed 24 non-polymorphic CNVs in 23 patients, among which 10 CNVs are known to be clinically relevant. Two rare deletions in 2q24.1q24.3, including KCNJ3 and 9q21.13 are novel pathogenic genetic loci and 12 CNVs are of unknown clinical significance. Our results further support the notion that rare CNVs can cause different types of epilepsy, emphasize the efficiency of detecting novel candidate genes by whole-genome array CGH, and suggest that the clinical application of array CGH should be extended to patients with unexplained epilepsies. © 2012 Wiley Periodicals, Inc.

Full-text

Available from: Hanna Mierzewska, Oct 20, 2014
1 Follower
 · 
167 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Copy number variants (CNVs) are deletions or duplications of DNA. CNVs have been increasingly recognized as an important source of both normal genetic variation and pathogenic mutation. Technologies for genome-wide discovery of CNVs facilitate studies of large cohorts of patients and controls to identify CNVs that cause increased risk for disease. Over the past 5 years, studies of patients with epilepsy confirm that both recurrent and non-recurrent CNVs are an important source of mutation for patients with various forms of epilepsy. Here, we will review the latest findings and explore the clinical implications.
    09/2014; 2(3):162-167. DOI:10.1007/s40142-014-0046-6
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BackgroundChromosomal microarray (CMA) is currently the first-tier genetic test for patients with idiopathic neuropsychiatric diseases in many countries. Its improved diagnostic yield over karyotyping and other molecular testing facilitates the identification of the underlying causes of neuropsychiatric diseases. In this study, we applied oligonucleotide array comparative genomic hybridization as the molecular genetic test in a Chinese cohort of children with DD/ID, autism or MCA.ResultsCMA identified 7 clinically significant microduplications and 17 microdeletions in 19.0% (20/105) patients, with size of aberrant regions ranging from 11 kb to 10.7 Mb. Fourteen of the pathogenic copy number variant (CNV) detected corresponded to well known microdeletion or microduplication syndromes. Four overlapped with critical regions of recently identified genomic syndromes. We also identified a rare de novo 2.3 Mb deletion at 8p21.3-21.2 as a pathogenic submicroscopic CNV. We also identified two novel CNVs, one at Xq28 and the other at 12q21.31-q21.33, in two patients (1.9%) with unclear clinical significance. Overall, the detection rate of CMA is comparable to figures previously reported for accurately detect submicroscopic chromosomal imbalances and pathogenic CNVs except mosaicism, balanced translocation and inversion.ConclusionsThis study provided further evidence of an increased diagnostic yield of CMA and supported its use as a first line diagnostic tool for Chinese individuals with DD/ID, ASD, and MCA.
    Molecular Cytogenetics 05/2014; 7:34. DOI:10.1186/1755-8166-7-34 · 2.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective To establish the genetic basis of Landau-Kleffner syndrome (LKS) in a cohort of two discordant monozygotic (MZ) twin pairs and 11 isolated cases.Methods We used a multifaceted approach to identify genetic risk factors for LKS. Array comparative genomic hybridization (CGH) was performed using the Agilent 180K array. Whole genome methylation profiling was undertaken in the two discordant twin pairs, three isolated LKS cases, and 12 control samples using the Illumina 27K array. Exome sequencing was undertaken in 13 patients with LKS including two sets of discordant MZ twins. Data were analyzed with respect to novel and rare variants, overlapping genes, variants in reported epilepsy genes, and pathway enrichment.ResultsA variant (cG1553A) was found in a single patient in the GRIN2A gene, causing an arginine to histidine change at site 518, a predicted glutamate binding site. Following copy number variation (CNV), methylation, and exome sequencing analysis, no single candidate gene was identified to cause LKS in the remaining cohort. However, a number of interesting additional candidate variants were identified including variants in RELN, BSN, EPHB2, and NID2.SignificanceA single mutation was identified in the GRIN2A gene. This study has identified a number of additional candidate genes including RELN, BSN, EPHB2, and NID2.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
    Epilepsia 05/2014; 55(6). DOI:10.1111/epi.12645 · 4.58 Impact Factor