15q13.3 microdeletions in a prospectively recruited cohort of patients with idiopathic generalized epilepsy in Bulgaria

Kirov, Andrey; Dimova, Petia; Тодорова, Албена; Mefford, Heather C; Todorov, Tihomir; Saraylieva, Gergana; Bojinova, V.; Mitev, Vanio; Helbig, Ingo

doi:10.1016/j.eplepsyres.2012.10.013

Cited by 8 publications

(4 citation statements)

References 15 publications

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“…Indeed, 12/1,223 (1 %) patients carried a 15q13.3 deletion compared to 0/3,699 control individuals [45••]. Several subsequent studies confirmed this finding [33, 47, 48], establishing the deletion as one of the most prevalent genetic risk factors for GGE with an estimated odds ratio of 68 (29–181) [47]. …”

Section: Recurrent Deletions In Epilepsymentioning

confidence: 98%

“…However, comparison of overlapping CNVs in similarly affected patients often reveals a “smallest region of overlap” that can highlight one or a few genes as primarily responsible for the phenotype. Examples include the discovery of CHD7 as the gene for CHARGE syndrome [17], EHMT1 as the critical gene in 9q34 deletions (Kleefstra syndrome) [18], and MBD5 in 2q23.1 deletions [48]. …”

Section: Copy Number Variants and Human Diseasementioning

confidence: 99%

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CNVs in Epilepsy

Mefford

2014

Curr Genet Med Rep

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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.

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Section: Recurrent Deletions In Epilepsymentioning

confidence: 98%

Section: Copy Number Variants and Human Diseasementioning

confidence: 99%

CNVs in Epilepsy

Mefford

2014

Curr Genet Med Rep

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“…Exome-based genetic screening studies have demonstrated that over twenty genes were associated with IGEs, such as CACNA1H , CACNB4 , CASR , CHD4 , CLCN2 , EFHC1 , GABRD , GABRA1 , GABRG2 , GABRB3 , HCN2 , KCC2 , KCNMA1 , RORB , SCN1A , SLC12A5 , SLC2A1 , RYR 2, and THBS1 ( DiFrancesco et al, 2011 ; Striano et al, 2012 ; Kahle et al, 2014 ; Rudolf et al, 2016 ; Santolini et al, 2017 ; Wang et al, 2017 ; Abou El Ella et al, 2018 ; Li et al, 2018 ; Yap and Smyth, 2019 ; Chan et al, 2020 ; Liu et al, 2021 ). Recent studies also identified several copy number variants associated with IGEs, such as duplication at 8q21.13-q22.2 and microdeletions at 1q21.1, 15q11.2, 15q13.3, and 16p13.11 ( de Kovel et al, 2010 ; Kirov et al, 2013 ; Møller et al, 2013 ; Jähn et al, 2014 ; Rezazadeh et al, 2017 ). Clinically, genetic etiologies in majority of the cases with IGEs remain unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies also identified several copy number variants associated with IGEs, such as duplication at 8q21.13-q22.2 and microdeletions at 1q21. 1, 15q11.2, 15q13.3, and 16p13.11 (de Kovel et al, 2010;Kirov et al, 2013;Møller et al, 2013;Jähn et al, 2014;Rezazadeh et al, 2017). Clinically, genetic etiologies in majority of the cases with IGEs remain unknown.…”

Section: Introductionmentioning

confidence: 99%

GRIN2A Variants Associated With Idiopathic Generalized Epilepsies

Liu

Lin

et al. 2021

Front. Mol. Neurosci.

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Objective: The objective of this study is to explore the role of GRIN2A gene in idiopathic generalized epilepsies and the potential underlying mechanism for phenotypic variation.Methods: Whole-exome sequencing was performed in a cohort of 88 patients with idiopathic generalized epilepsies. Electro-physiological alterations of the recombinant N-methyl-D-aspartate receptors (NMDARs) containing GluN2A mutants were examined using two-electrode voltage-clamp recordings. The alterations of protein expression were detected by immunofluorescence staining and biotinylation. Previous studies reported that epilepsy related GRIN2A missense mutations were reviewed. The correlation among phenotypes, functional alterations, and molecular locations was analyzed.Results: Three novel heterozygous missense GRIN2A mutations (c.1770A > C/p.K590N, c.2636A > G/p.K879R, and c.3199C > T/p.R1067W) were identified in three unrelated cases. Electrophysiological analysis demonstrated R1067W significantly increased the current density of GluN1/GluN2A NMDARs. Immunofluorescence staining indicated GluN2A mutants had abundant distribution in the membrane and cytoplasm. Western blotting showed the ratios of surface and total expression of the three GluN2A-mutants were significantly increased comparing to the wild type. Further analysis on the reported missense mutations demonstrated that mutations with severe gain-of-function were associated with epileptic encephalopathy, while mutations with mild gain of function were associated with mild phenotypes, suggesting a quantitative correlation between gain-of-function and phenotypic severity. The mutations located around transmembrane domains were more frequently associated with severe phenotypes and absence seizure-related mutations were mostly located in carboxyl-terminal domain, suggesting molecular sub-regional effects.Significance: This study revealed GRIN2A gene was potentially a candidate pathogenic gene of idiopathic generalized epilepsies. The functional quantitative correlation and the molecular sub-regional implication of mutations helped in explaining the relatively mild clinical phenotypes and incomplete penetrance associated with GRIN2A variants.

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Genetics of Psychiatric Disorders: Advances in Genetic Epidemiology and Molecular Genetics

Merikangas

Karayiorgou

2015

Psychiatry

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15q13.3 microdeletions in a prospectively recruited cohort of patients with idiopathic generalized epilepsy in Bulgaria

Cited by 8 publications

References 15 publications

CNVs in Epilepsy

CNVs in Epilepsy

GRIN2A Variants Associated With Idiopathic Generalized Epilepsies

Genetics of Psychiatric Disorders: Advances in Genetic Epidemiology and Molecular Genetics

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