Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 133(Pt 1):23-32

Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Brain (Impact Factor: 9.2). 10/2009; 133(Pt 1):23-32. DOI: 10.1093/brain/awp262
Source: PubMed


Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8-13.2; chi(2) = 26.7; 1 degree of freedom; P = 2.4 x 10(-7)). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8-13.2; P = 4.2 x 10(-4)) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3-74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.

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    • "Two other recurrent deletions have been firmly associated with epilepsy. De Kovel and colleagues investigated a cohort of 1,234 individuals with GGE and 3,022 controls for recurrent CNVs [49]. In addition to 15q13.3 deletions, they found recurrent deletions at 16p13.11 (chr16: 15,500,000–16,300,000, hg19) and 15q11.2 "
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    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
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    • "including the region between breakpoints (BP) 1–2. A number of case–control studies have demonstrated that this deletion is enriched in cases as compared to controls [15•–17]. Nonetheless, the fact that it has been observed in control individuals and unaffected relatives, coupled with the broad spectrum of associated phenotypes (developmental delay [15•, 16], schizophrenia [18], epilepsy [17, 19], etc.), has anecdotally resulted in some hesitances to classify it as “pathogenic.” "
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    ABSTRACT: One of the most fundamental goals of the study of human genetics was to determine the relationship between genomic variation and human disease. The effects of large-scale structural variation, such as aneuploidy and other cytogenetically visible imbalances, as well as sequence-level variation, have been studied for several decades. However, compared to these, the impact of submicroscopic copy number variants (CNV) has only recently been appreciated. Despite this, lessons learned from the study of CNVs have already proven significant and broadly applicable. From expanding the concept of normal human variation to providing concrete examples of the utility of genomics in clinical care and challenging notions of the genetic architecture of complex disease, CNVs have provided valuable insights into the genomics of human health and development.
    09/2014; 2(3). DOI:10.1007/s40142-014-0048-4
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    • "These patients do not have PWS and share several features including different degrees of learning disability, delayed motor and speech development, dysmorphisms and behavioral problems (ADHD, autism, obsessive-compulsive behavior). Two studies reported patients affected by schizophrenia (Stefansson et al., 2008; Kirov et al., 2009) and in one case by epilepsia (De Kovel et al., 2010), while another group recently published a deletion of BP1–BP2 in two young patients affected only by ID and several dysmorphic features (Madrigal et al., 2012). These results suggest that the genes located between the BP1–BP2 breakpoints are determining behavior and intellectual abilities (Bittel et al., 2006). "
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